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Haemolytic uraemic syndrome
SYMPOSIUM: NEPHROLOGY
Haemolytic uraemic syndrome
Definition The Swiss haematologist Conrad von Gasser first described HUS in 1955. He used the term to describe the combined symptoms of diarrhoea, haemolytic anaemia, thrombocytopaenia and acute kidney injury (AKI), which he observed in five children. Haemolytic anaemia is defined as a haemoglobin level less than 100 g/l and fragmented erythrocytes on blood film. Thrombocytopaenia occurs when the platelet count is less than 150 109/l, and AKI with serum creatinine greater than the agerelated range (more than 97th percentile) or glomerular filtration rate (GFR) less than 80 ml/min/1.73 m2 by the Schwartz formula. This description is still valid today however HUS is further subdivided in to two broad categories: Typical, usually diarrhoea positive D þ HUS (more than 90% of cases) Atypical, usually diarrhoea negative D HUS or aHUS (approximately 5% of cases) The common causes of each category are listed in Table 1. The D þ HUS is the most common cause of AKI in childhood.
Amrit Kaur Larissa Kerecuk
Abstract Haemolytic uraemic syndrome (HUS) is the most common cause of acute kidney injury (AKI) in children. It is categorized by a triad of clinical features, haemolytic anaemia, thrombocytopaenia and AKI. HUS is subdivided into two broad categories, diarrhoea positive HUS (more than 90% of cases) most commonly caused by Shiga toxin (Stx)-producing Escherichia coli (also called verotoxin) and the less common diarrhoea negative HUS. HUS is initiated by intestinal colonization with Stx-producing bacteria. HUS results in widespread thrombotic microangiopathy (TMA) in renal glomeruli, the gastrointestinal tract, the brain, and the pancreas. The aim of this review is to summarise the latest developments in our understanding of this condition, focussing on epidemiology, pathophysiology and disease course.
Keywords Acute kidney injury; haemolytic uraemic syndrome;
Epidemiology
pneumococcal haemolytic uraemic syndrome; shiga toxin; thrombotic microangiopathy
The incidence of HUS is greatest in children under 5 years old and then peaks again in the elderly. Studies suggest greatest risk of developing HUS is in areas with high density of cattle. There is a seasonal variation with majority of cases occurring in the summer months. Infections with Shiga toxin (Stx)-producing Escherichia coli (STEC; also called verotoxin, VTEC) is the greatest risk factor. E. coli 0157:H7 is the most prevalent serotype of STEC associated with human disease worldwide. STEC colonises animals without causing disease. STEC are not part of the normal human gut flora and transmission occurs mainly through ingestion of infected food or water, person to person spread and animal contact. Contaminated ground beef, unpasteurised milk products, vegetables, drinking water and petting of farm animals have been the source of infection in previous outbreaks. Isolated cases can also occur. Inoculation with 100 organisms is sufficient enough to cause disease. The incubation period is 1 e8 days, although asymptomatic infection may occur. Shedding of the bacterium may persist for more than 3 weeks after infection. Approximately 10% of children exposed to STEC will develop gastrointestinal symptoms. Of these children, 3e7% (isolated cases) or up to 20% in outbreaks will develop HUS.
How common? UK and worldwide The overall incidence of haemolytic uraemic syndrome (HUS) in UK and Ireland is 0.71 per 100,000 children under 16 years of age. A prospective surveillance study of childhood HUS from 1997 to 2001 in UK and Ireland showed the highest incidence rates were in Scotland (1.56 per 100,000). The precise reason for this regional variation is unknown but this difference could be secondary to the relative population densities of livestock and humans and reliance on private water supplies in rural areas. The prevalence of HUS has remained unchanged since 1985. The incidence is similar across Europe, Australia and North America. Argentina is reported to have the highest incidence worldwide, 22 per 100,000. HUS occurs sporadically in human populations with outbreaks occurring infrequently. The largest outbreak in recent history was in Germany in 2011, and was traced backwards to a rare Shiga toxin producing strain of Escherichia coli, E. Coli 0104:H4. The majority of affected individuals in this outbreak were adult females. Following post outbreak surveillance consumption of fenugreek sprouts was attributed but other vegetables were also implicated. All sufferers had resided or visited north Germany before becoming symptomatic.
Pathology, pathogenesis and applied physiology Understanding of the pathogenesis of HUS provides and explanation for the clinical course and facilitates a logical approach to treatment. Histologically, HUS results in thrombotic microangiopathy (TMA) in renal glomeruli, the gastrointestinal tract, brain and pancreas. TMA is characterized by vessel wall thickening at the arteriolarecapillary junction, with swelling or detachment from the basement membrane and intraluminal thrombosis that leads to partial or complete obstruction of the vessel lumen.
Amrit Kaur MB ChB MRCPCH BSc Hons is a Consultant Paediatric Nephrologist at Royal Manchester Children’s Hospital, Manchester, UK. Conflict of interest: none. Larissa Kerecuk MBBS BSc MRCPCH FRCPCH is Rare Disease Lead, Consultant Paediatric Nephrologist at Birmingham Children’s Hospital, Birmingham, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH --:-
1
Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaur A, Kerecuk L, Haemolytic uraemic syndrome, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.04.003
SYMPOSIUM: NEPHROLOGY
circulates bound to platelets, monocytes, neutrophils, as well as leucocyte complexes. The leucocytes used for transport are resistant to Stx associated cell damage therefore promote the spread of the toxin to distant sites. The finding of leucocytosis is a poor prognostic factor in HUS. During the illness, platelets adhere to injured endothelium resulting in TMA. Multiple microthrombi lead to thrombocytopaenia. Stx induces tissue factor expression on endothelial cells, which is a receptor for coagulation factor VII. Via the extrinsic coagulation pathway, factor X is converted to Xa, which in turn promotes clot formation and further platelet activation. Haemolysis of erythrocytes is less well understood and is assumed as a result of mechanical damage secondary to movement through occluded blood vessels. Once transported from the intestines the main target organ is the kidney. Glomerular and tubular cells are damaged during the acute infection as Stx has a cytotoxic and apoptotic effect on glomerular endothelial and epithelial cells. The pathophysiology of atypical HUS depends on the aetiology. Endothelial cell insult and damage is the histopathological manifestation regardless of cause. This may be caused by drugs, autoimmune or genetic mechanisms. In pneumococcal HUS, neuraminidase produced by pneumococcus exposes the T Antigen on erythrocytes which is then bound by pre-existing IgM antibodies and haemolysis.
Some causes of HUS depending on category type Typical HUS
Atypical HUS
Infectious causes Infectious causes C C Escherichia coli Streptococcus pneumoniae C Shigella Inherited forms C Complement abnormalities dystenteriae C Citrobacter freundii C Von Willebrand factor-cleaving protease constitutional deficiency C Cobalamin metabolism defect Autoimmune C Systemic lupus erythematosus C Scleroderma C Antiphospholipid syndrome Drugs C Cyclosporine A, tacrolimus C Cytotoxic drugs C Quinine C Oral contraceptives Other C Autosomal dominant and recessive types C Cancer associated C Pregnancy C Post renal transplant C HIV associated
Course of the disease After the initial incubation period D þ HUS is usually preceded by gastroenteritis with bloody or watery diarrhoea (90% of cases), abdominal cramps, nausea and vomiting (50% of cases). The intestinal symptoms can lead to haemorrhagic colitis, colonic gangrene or perforation. Within 2 weeks of the intestinal symptoms the child develops pallor and jaundice secondary to haemolysis. Thrombocytopaenia is found on full blood count and clinically may manifest itself as petechiae or bleeding from mucosal surfaces. Renal involvement leads to oliguria/anuria, hypertension (20e30% of cases) and oedema. Renal involvement is typically seen between days 4 and 7 after the onset of diarrhoea. Fever is not usually a presenting symptom but the child may have a history of low grade pyrexia prior to presenting. Central nervous involvement can occur in up to 20% of children. Symptoms range can from irritability, seizures to cerebral encephalopathy. In a small percentage of children cardiomyopathy and pancreatitis may also be a feature. Please refer to Table 2 for a list of clinical features associated with each system involved. The duration of symptoms is variable, most commonly lasting 1e3 weeks. Improvement is usually accompanied by a rise in platelet count which typically precedes renal function recovery.
Table 1
HUS begins with intestinal colonization of STEC. Attachment of STEC to host intestinal enterocytes is aided by bacterial proteins. This causes destruction of microvilli and the symptom of watery diarrhoea. Further translocation of bacterial proteins from STEC into host enterocytes causes disturbance of cell structure and function. The role of Stx is vital in the virulence of STEC. The toxin has two subunits, designated A and B. The A subunit has enzyme activity whilst the pentamer B subunit binds specifically to glycosphingolipid receptor (Gb3) on host cells. STEC have bacteriophages that encode Stx, strains can encode for more than one Stx if they process the specific bacteriophage. The E. coli 0104:H4 outbreak in Germany in 2011 was caused by an enteroaggressive E. coli that had acquired Shiga-toxin producing bacteriophages. Importantly, antibiotics can cause the release of these toxins hence the use of antibiotics is relatively contraindicated in the treatment of HUS Binding of the toxin to Gb3 causes internalization of the A subunit, this is then cleaved into two parts. The A1 binds to ribosomes and disrupts protein synthesis causing cell death. The Gb3 receptor is found on glomerular endothelium, brain and pancreatic cells. The Gb3 receptor distribution helps to explain some of the clinical symptoms found in HUS. The presence of Stx in the intestinal lumen is also thought to trigger presence of inflammatory mediators (cytokines, interleukins) that cause endothelial damage and further promote platelet adhesion to the subendothelium. Damage to the intestinal epithelium allows Stx to enter the circulation in addition to causing local damage. Stx
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Diagnosis, history and physical examination In order to make the diagnosis a standard paediatric history together with emphasis on fluid balance is essential. Specifically ask about gastrointestinal symptoms, the tolerance of oral fluids and ongoing losses including urine output. Exploration of ingestion of infected food products, farm animal contact and person to person spread is essential.
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Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaur A, Kerecuk L, Haemolytic uraemic syndrome, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.04.003
SYMPOSIUM: NEPHROLOGY
Urine albumin and creatinine ratio, assessment of glomerular leak Stool microscopy and culture STEC/VTEC serology If patient presents with severe abdominal signs, chest and abdominal X-rays especially erect films looking for signs of perforation must be performed. Abdominal ultrasound is helpful to exclude preceding renal structural abnormalities, pancreatitis and liver involvement. Further imaging including CT abdomen and MRI brain may be required depending on clinical status and neurology. Renal biopsy is very rarely indicated in typical HUS. If performed TMA in more than 50% of glomeruli has the worst prognosis. Renal cortical necrosis is seen if arterial thrombosis is severe. In aHUS, the investigations are slightly more complex and early involvement of tertiary paediatric nephrology services is advised. Specialist investigations will include, complement levels/activity, Factor H concentrations, plasma vWF protease activity, metabolic disease investigations and autoimmune antibody screen. Treatment of aHUS is supportive and includes plasma exchange and early use of a humanized monoclonal antibody that is a terminal complement inhibitor (Eculizumab). The latter treatment has transformed the prognosis of this condition.
List of clinical features associated with HUS System involvement Clinical features Gastrointestinal
Haematology
Renal
Central nervous
Cardiac
Pancreas
Bloody or watery diarrhoea Abdominal cramps Nausea and/or vomiting Rectal prolapse Intussusception Toxic dilatation of colon Bowel perforation Petechiae Mucosal bleeding Jaundice Oliguria or anuria Hypo or hypervolaemia Hypovolaemic shock Hypertension Oedema Lethargy Irritability Seizures Cranial nerve palsy Cerebral oedema Encephalopathy Abnormal posturing Coma Cardiomyopathy Arrhythmias secondary to electrolyte disturbances Myocarditis and tamponade Diabetes mellitus Pancreatitis
Differential diagnosis Thrombotic thrombocytopaenic purpura (TTP) is a condition classified by microangiopathic haemolytic anaemia, thrombocytopaenia, nephropathy, fever and neurological symptoms associated with mutations in the von Willebrand cleaving protease. Other differentials include disseminated intravascular coagulation, sepsis, systemic lupus erythematosus and vasculitis.
Management
Table 2
There is no specific treatment for D þ HUS. Early diagnosis and supportive care is fundamental to clinical recovery. Early involvement of specialist paediatric nephrology advice is also beneficial. These children should be nursed in isolation to prevent secondary transmission. HUS is a notifiable disease and local procedures for contacting Health Protection Agency should be adhered to. Treatment in atypical HUS may include plasmapheresis for complement dysregulation causes and intravenous antibiotics in Streptococcus pneumoniae associated HUS, which in comparison to D þ HUS is not routinely recommended.
Examination should include height, weight and body surface area calculation. Vital signs including blood pressure must be measured. In view of potential complications of HUS, the cardiovascular, respiratory, abdominal, and central nervous systems should be examined, paying particular attention to hydration status and acute abdominal signs. Regular examination during hospital admission is essential.
Investigations Initial inpatient investigations should include the following: FBC and film, assessment of anaemia, thrombocytopaenia and erythrocyte fragmentation Urea and electrolytes Liver and bone function Bicarbonate, assessment of acid-base status Blood glucose and amylase, assess pancreatic involvement Lactate dehydrogenase or haptoglobulin, index of degree of haemolysis Clotting screen Group and save, blood transfusion may be required Urine dipstick for blood and protein Urine microscopy and culture
PAEDIATRICS AND CHILD HEALTH --:-
General considerations The majority of all children with D þ HUS develop some degree of renal impairment. Approximately two thirds will require renal replacement therapy (RRT e see below). For those children who do not require dialysis, fluid management is key to a successful outcome. Regular assessment of hydration status, twice daily weights, strict fluid balance and regular electrolyte measurements including serum glucose are required. Daily fluid replacement regimen should include insensible losses (400 ml/ m2/day) plus total 24 hour urine output, emphasis is on maintaining euvolaemia in the acute phase. The choice of
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Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaur A, Kerecuk L, Haemolytic uraemic syndrome, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.04.003
SYMPOSIUM: NEPHROLOGY
intravascular fluid replacement should be governed by plasma electrolytes. Packed red cell transfusion may be required in those with a haemoglobin less than 70 g/l or symptomatic anaemia. Careful monitoring is required in view of potential fluid overload and hyperkalaemia secondary to blood transfusion. Platelet transfusions are generally not required. If the platelet count is particularly low (less than 10 109/l), if there are episodes of active bleeding or pre-operative correction is required then transfusions may be given. Careful monitoring and treatment of hypertension should not be overlooked in the management of these children. In the acute phase, if hypertension persists after fluid overload has been dealt with, antihypertensive therapy should be started with calciumchannel blockers. Once, renal function has improved and if hypertension is persistent, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) are particularly useful especially if there is also proteinuria. Seizures in central nervous disease should be managed in accordance with advance paediatric life support (APLS) algorithms ensuring that electrolyte, metabolic abnormalities and intracranial lesions have been excluded.
management unless there is evidence of sepsis which must be treated aggressively. Plasma infusions and therapeutic plasma exchange have no proven beneficial role in D þ HUS although there are limited studies to support the use of plasma exchange in D þ HUS with central nervous system involvement. Future treatment options Anti-Shiga toxin antibodies have been shown to prevent HUS in animals. The monoclonal antibodies are intended to neutralize the circulating Stx. When healthy adults have been exposed to monoclonal antibodies, no serious adverse events were reported. In 2003 a randomized, double blind, placebo-controlled study was initiated in Canada and Argentina. Children with STEC positive stools were randomized. Children were treated within 72 hours of the onset of bloody diarrhoea and then followed up for 4 months. The study concentrated on the safety and pharmokinetics of the humanised monoclonal antibody (Urtoazumab) as a therapy against paediatric patients infected with Shiga toxin. The study showed no serious adverse effects of administering the monoclonal antibody and there was no evidence of human antibodies against the monoclonal antibody after treatment. No comment was made on the clinical benefit of administering Urtoazumab in paediatric patients with D þ HUS. Eculizumab is a monoclonal antibody against complement factor 5 and has been used in the recent DþHUS outbreak in Germany with anecdotal reports of benefit. However, a RCT is required to establish its usefulness in this setting.
Renal replacement therapy RRT is required in those children who are fluid overloaded in presence of oliguria, correction of electrolyte or acid-base disturbances and symptomatic uraemia. Common electrolyte disturbance include hyperkalaemia and hyponatraemia. Fluid overload can lead on to pulmonary oedema and myocardial insufficiency. The type of RRT offered is governed by clinical and logistic factors. Peritoneal dialysis (PD) has the advantage of avoiding large volume imbalances. Disadvantages include the need for surgical placement of PD catheter. This may not be possible in view of acute abdominal signs or impede ultrafiltration in during acute enterocolitis. Haemodialysis (HD) has the advantages of potentially being available without the need for abdominal surgery however central venous catheters must be placed in order to perform HD. Disadvantages include the need for anticoagulation, haemodynamic instability and additional loss of blood and platelets in the extracorporeal circulation. Continuous haemofiltration can be instituted in cases of haemodynamic instability.
Prognosis and explanation to patient D þ HUS generally has a good prognosis. Early recognition and treatment including dialysis has improved disease outcomes. Acute mortality rate is 1e4% in D þ HUS. Long term complications after initial disease are seen in approximately 20e40% of patients. Complications include persistent proteinuria (15e30% of cases), arterial hypertension (5e15%), neurological impairment, diabetes mellitus, and chronic renal failure (9e18%). End stage renal failure occurs in 3% of these children. Poor prognostic factors for long term renal complications include; leucocytosis more than 20 109/l with neutrophilia shock during acute illness anuria for more than 5e14 days, more than 10 days worst outcome dialysis for more than 4 weeks is unlikely to lead to full renal recovery hypertension persistent proteinuria central nervous involvement severe colitis and/or rectal prolapse cortical necrosis and TMA (more than 50% glomeruli involved) on renal biopsy atypical HUS It is important to follow up cases of even mild HUS. In a study in which 130 children with D þ HUS not requiring dialysis during the acute illness, 3.8% and 11.5% had proteinuria or hypertension, respectively. Nearly one fifth had microalbuminuria after 12 years from the onset of disease.
Other treatments Nutritional support and early involvement of dietetic support is particularly important to prevent a catabolic state during protracted illnesses. Antimotility agents and nonsteroidal antiinflammatory analgesics (NSAIDs) are not recommended in the management of D þ HUS. Antimotility agents have been associated with higher rates of HUS and NSAIDs increase the risk of gastrointestinal bleeding and reduce renal perfusion thereby affecting GFR. Antibiotics are not recommended as part of the treatment. Experimental data has shown certain classes of antibiotics, trimethoprim, sulfamethoxazole, and quinolones stimulate the bacterial Shiga toxin expression and release. Other studies have shown antibiotic administration does not increase the risk of HUS. In view of the disparity between studies the general consensus is not to administer antibiotics as part of routine
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Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaur A, Kerecuk L, Haemolytic uraemic syndrome, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.04.003
SYMPOSIUM: NEPHROLOGY
In D HUS, renal prognosis is significantly worse, with nearly half of children developing end-stage renal failure (ESRF) and a quarter dying in the acute period. Renal transplantation in D þ HUS children has low recurrence risk of original illness. In D HUS depending on the aetiology, recurrence of illness in transplanted organ may be extremely high especially in factor deficiencies.
Karpman D, Sartz L, Johnson S. Pathophysiology of typical hemolytic uremic syndrome. Semin Thromb Hemost 2010; 36: 575e85. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 2016; 31: 15e39. Lynn RM, O’Brien SJ, Taylor CM, et al. Childhood hemolytic uremic syndrome, United Kingdom and Ireland. Emerg Infect Dis April 2005; 11: 590e6. Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol July 2010; 5: 1218e28. Rees L, Webb NJA, Brogan PA. Haemolytic uraemic syndrome. Oxford specialist handbooks in paediatrics: paediatric nephrology. Oxford: Oxford University Press, 2007; 384e91. Scheiring J, Andreoli SP, Zimmerhacki LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 2008; 23: 1749e60. Scheiring J, Rosales A, Zimmerhackl LB. Today’s understanding of the haemolytic uraemic syndrome. Eur J Pediatr January 2010; 169: 7e13. Spinale JM, Ruebner RL, Copelovitch L, Kaplan BS. Long term outcomes of Shiga toxin hemolytic uremic syndrome. Pediatr Nephrol 2013; 28: 2097e105. Waters AM, Kerecuk L, Luk D, et al. Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United kingdom experience. J Pediatr August 2007; 151: 140e4. Werber FCD, Cramer JP, ASkar M, et al. Epidermic profile of Shigatoxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 2011; 365: 1771e80.
Follow up Subsequent medical follow up after the initial admission will depend on the severity of the disease. Those who have had a milder form of HUS should be seen soon after discharge and then annually to monitor for hypertension and proteinuria. This service can be offered by the local paediatrician or general practitioner. Early referral to paediatric nephrologist is recommended should the annual review highlight a concern. Of those children that have had a more protracted illness, they will remain under the care of the paediatric renal services and other specialists depending on the complications of their illness.
Prevention Hygienic measures are the most important factor in preventing the disease. Avoiding ingestion of contaminated food by assuring thorough cooking of meat products, correct pasteurisation of dairy products, and vegetables/fruit to be washed thoroughly. Young children should avoid consumption of unpasteurised food products. It seems extreme to prohibit the petting of farm animals, however hand washing should be encouraged afterwards. Person to person spread amongst children who attend nursery again can be limited by ensuring adequate hand hygiene during toileting. Referral to Health Protection Agency should be done early as soon as diagnosis is suspected. A
Practice points C
FURTHER READING Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol April 2009; 24: 687e96. Bitzan M, Schaefer F, Reymond D. Treatment of typical (enteropathic) hemolytic uremic syndrome. Semin Thromb Hemost September 2010; 36: 594e610. Garg AX, Suri RS, Barrowman N, et al. Long-term renal prognosis of diarrhea-associated haemolytic uremic syndrome. JAMA September 10, 2003; 290: 1360e70. Gianviti A, Tozzi AE, De Petris L. Risk factors for poor renal prognosis in children with hemolytic uremic syndrome. Pediatr Nephrol December 2003; 18: 1229e35. Grisaru S. Management of hemolytic uremic syndrome in children. Int J Nephrol Renov Dis 2014; 7: 231e9. Karpman D. Haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Curr Paediatr 2002; 12: 569e74.
PAEDIATRICS AND CHILD HEALTH --:-
C
HUS is the combined symptoms of diarrhoea, haemolytic anaemia, thrombocytopaenia and acute kidney injury (AKI). Typical HUS, usually diarrhoea positive D þ HUS (more than 90% of cases), atypical HUS, usually diarrhoea negative D HUS or aHUS (approximately 5% of cases) The D þ HUS is the most common cause of AKI in childhood
Duration of symptoms to recovery is variable, usually occurring 1e3 weeks after onset. Onset of improvement is accompanied by a rise in platelet count. C
C
C
5
There is no specific treatment for D þ HUS. Antibiotics can cause the release of toxins hence the use of antibiotics is relatively contraindicated in the treatment of HUS. Renal replacement therapy (RRT) is required in those children who are fluid overloaded in presence of oliguria, correction of electrolyte or acid-base disturbances and symptomatic uraemia Long term complications after initial disease are seen in approximately 20e40% of patients
Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaur A, Kerecuk L, Haemolytic uraemic syndrome, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.04.003
Haemolytic uraemic syndrome
Definition The Swiss haematologist Conrad von Gasser first described HUS in 1955. He used the term to describe the combined symptoms of diarrhoea, haemolytic anaemia, thrombocytopaenia and acute kidney injury (AKI), which he observed in five children. Haemolytic anaemia is defined as a haemoglobin level less than 100 g/l and fragmented erythrocytes on blood film. Thrombocytopaenia occurs when the platelet count is less than 150 109/l, and AKI with serum creatinine greater than the agerelated range (more than 97th percentile) or glomerular filtration rate (GFR) less than 80 ml/min/1.73 m2 by the Schwartz formula. This description is still valid today however HUS is further subdivided in to two broad categories: Typical, usually diarrhoea positive D þ HUS (more than 90% of cases) Atypical, usually diarrhoea negative D HUS or aHUS (approximately 5% of cases) The common causes of each category are listed in Table 1. The D þ HUS is the most common cause of AKI in childhood.
Amrit Kaur Larissa Kerecuk
Abstract Haemolytic uraemic syndrome (HUS) is the most common cause of acute kidney injury (AKI) in children. It is categorized by a triad of clinical features, haemolytic anaemia, thrombocytopaenia and AKI. HUS is subdivided into two broad categories, diarrhoea positive HUS (more than 90% of cases) most commonly caused by Shiga toxin (Stx)-producing Escherichia coli (also called verotoxin) and the less common diarrhoea negative HUS. HUS is initiated by intestinal colonization with Stx-producing bacteria. HUS results in widespread thrombotic microangiopathy (TMA) in renal glomeruli, the gastrointestinal tract, the brain, and the pancreas. The aim of this review is to summarise the latest developments in our understanding of this condition, focussing on epidemiology, pathophysiology and disease course.
Keywords Acute kidney injury; haemolytic uraemic syndrome;
Epidemiology
pneumococcal haemolytic uraemic syndrome; shiga toxin; thrombotic microangiopathy
The incidence of HUS is greatest in children under 5 years old and then peaks again in the elderly. Studies suggest greatest risk of developing HUS is in areas with high density of cattle. There is a seasonal variation with majority of cases occurring in the summer months. Infections with Shiga toxin (Stx)-producing Escherichia coli (STEC; also called verotoxin, VTEC) is the greatest risk factor. E. coli 0157:H7 is the most prevalent serotype of STEC associated with human disease worldwide. STEC colonises animals without causing disease. STEC are not part of the normal human gut flora and transmission occurs mainly through ingestion of infected food or water, person to person spread and animal contact. Contaminated ground beef, unpasteurised milk products, vegetables, drinking water and petting of farm animals have been the source of infection in previous outbreaks. Isolated cases can also occur. Inoculation with 100 organisms is sufficient enough to cause disease. The incubation period is 1 e8 days, although asymptomatic infection may occur. Shedding of the bacterium may persist for more than 3 weeks after infection. Approximately 10% of children exposed to STEC will develop gastrointestinal symptoms. Of these children, 3e7% (isolated cases) or up to 20% in outbreaks will develop HUS.
How common? UK and worldwide The overall incidence of haemolytic uraemic syndrome (HUS) in UK and Ireland is 0.71 per 100,000 children under 16 years of age. A prospective surveillance study of childhood HUS from 1997 to 2001 in UK and Ireland showed the highest incidence rates were in Scotland (1.56 per 100,000). The precise reason for this regional variation is unknown but this difference could be secondary to the relative population densities of livestock and humans and reliance on private water supplies in rural areas. The prevalence of HUS has remained unchanged since 1985. The incidence is similar across Europe, Australia and North America. Argentina is reported to have the highest incidence worldwide, 22 per 100,000. HUS occurs sporadically in human populations with outbreaks occurring infrequently. The largest outbreak in recent history was in Germany in 2011, and was traced backwards to a rare Shiga toxin producing strain of Escherichia coli, E. Coli 0104:H4. The majority of affected individuals in this outbreak were adult females. Following post outbreak surveillance consumption of fenugreek sprouts was attributed but other vegetables were also implicated. All sufferers had resided or visited north Germany before becoming symptomatic.
Pathology, pathogenesis and applied physiology Understanding of the pathogenesis of HUS provides and explanation for the clinical course and facilitates a logical approach to treatment. Histologically, HUS results in thrombotic microangiopathy (TMA) in renal glomeruli, the gastrointestinal tract, brain and pancreas. TMA is characterized by vessel wall thickening at the arteriolarecapillary junction, with swelling or detachment from the basement membrane and intraluminal thrombosis that leads to partial or complete obstruction of the vessel lumen.
Amrit Kaur MB ChB MRCPCH BSc Hons is a Consultant Paediatric Nephrologist at Royal Manchester Children’s Hospital, Manchester, UK. Conflict of interest: none. Larissa Kerecuk MBBS BSc MRCPCH FRCPCH is Rare Disease Lead, Consultant Paediatric Nephrologist at Birmingham Children’s Hospital, Birmingham, UK. Conflict of interest: none.
PAEDIATRICS AND CHILD HEALTH --:-
1
Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaur A, Kerecuk L, Haemolytic uraemic syndrome, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.04.003
SYMPOSIUM: NEPHROLOGY
circulates bound to platelets, monocytes, neutrophils, as well as leucocyte complexes. The leucocytes used for transport are resistant to Stx associated cell damage therefore promote the spread of the toxin to distant sites. The finding of leucocytosis is a poor prognostic factor in HUS. During the illness, platelets adhere to injured endothelium resulting in TMA. Multiple microthrombi lead to thrombocytopaenia. Stx induces tissue factor expression on endothelial cells, which is a receptor for coagulation factor VII. Via the extrinsic coagulation pathway, factor X is converted to Xa, which in turn promotes clot formation and further platelet activation. Haemolysis of erythrocytes is less well understood and is assumed as a result of mechanical damage secondary to movement through occluded blood vessels. Once transported from the intestines the main target organ is the kidney. Glomerular and tubular cells are damaged during the acute infection as Stx has a cytotoxic and apoptotic effect on glomerular endothelial and epithelial cells. The pathophysiology of atypical HUS depends on the aetiology. Endothelial cell insult and damage is the histopathological manifestation regardless of cause. This may be caused by drugs, autoimmune or genetic mechanisms. In pneumococcal HUS, neuraminidase produced by pneumococcus exposes the T Antigen on erythrocytes which is then bound by pre-existing IgM antibodies and haemolysis.
Some causes of HUS depending on category type Typical HUS
Atypical HUS
Infectious causes Infectious causes C C Escherichia coli Streptococcus pneumoniae C Shigella Inherited forms C Complement abnormalities dystenteriae C Citrobacter freundii C Von Willebrand factor-cleaving protease constitutional deficiency C Cobalamin metabolism defect Autoimmune C Systemic lupus erythematosus C Scleroderma C Antiphospholipid syndrome Drugs C Cyclosporine A, tacrolimus C Cytotoxic drugs C Quinine C Oral contraceptives Other C Autosomal dominant and recessive types C Cancer associated C Pregnancy C Post renal transplant C HIV associated
Course of the disease After the initial incubation period D þ HUS is usually preceded by gastroenteritis with bloody or watery diarrhoea (90% of cases), abdominal cramps, nausea and vomiting (50% of cases). The intestinal symptoms can lead to haemorrhagic colitis, colonic gangrene or perforation. Within 2 weeks of the intestinal symptoms the child develops pallor and jaundice secondary to haemolysis. Thrombocytopaenia is found on full blood count and clinically may manifest itself as petechiae or bleeding from mucosal surfaces. Renal involvement leads to oliguria/anuria, hypertension (20e30% of cases) and oedema. Renal involvement is typically seen between days 4 and 7 after the onset of diarrhoea. Fever is not usually a presenting symptom but the child may have a history of low grade pyrexia prior to presenting. Central nervous involvement can occur in up to 20% of children. Symptoms range can from irritability, seizures to cerebral encephalopathy. In a small percentage of children cardiomyopathy and pancreatitis may also be a feature. Please refer to Table 2 for a list of clinical features associated with each system involved. The duration of symptoms is variable, most commonly lasting 1e3 weeks. Improvement is usually accompanied by a rise in platelet count which typically precedes renal function recovery.
Table 1
HUS begins with intestinal colonization of STEC. Attachment of STEC to host intestinal enterocytes is aided by bacterial proteins. This causes destruction of microvilli and the symptom of watery diarrhoea. Further translocation of bacterial proteins from STEC into host enterocytes causes disturbance of cell structure and function. The role of Stx is vital in the virulence of STEC. The toxin has two subunits, designated A and B. The A subunit has enzyme activity whilst the pentamer B subunit binds specifically to glycosphingolipid receptor (Gb3) on host cells. STEC have bacteriophages that encode Stx, strains can encode for more than one Stx if they process the specific bacteriophage. The E. coli 0104:H4 outbreak in Germany in 2011 was caused by an enteroaggressive E. coli that had acquired Shiga-toxin producing bacteriophages. Importantly, antibiotics can cause the release of these toxins hence the use of antibiotics is relatively contraindicated in the treatment of HUS Binding of the toxin to Gb3 causes internalization of the A subunit, this is then cleaved into two parts. The A1 binds to ribosomes and disrupts protein synthesis causing cell death. The Gb3 receptor is found on glomerular endothelium, brain and pancreatic cells. The Gb3 receptor distribution helps to explain some of the clinical symptoms found in HUS. The presence of Stx in the intestinal lumen is also thought to trigger presence of inflammatory mediators (cytokines, interleukins) that cause endothelial damage and further promote platelet adhesion to the subendothelium. Damage to the intestinal epithelium allows Stx to enter the circulation in addition to causing local damage. Stx
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Diagnosis, history and physical examination In order to make the diagnosis a standard paediatric history together with emphasis on fluid balance is essential. Specifically ask about gastrointestinal symptoms, the tolerance of oral fluids and ongoing losses including urine output. Exploration of ingestion of infected food products, farm animal contact and person to person spread is essential.
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SYMPOSIUM: NEPHROLOGY
Urine albumin and creatinine ratio, assessment of glomerular leak Stool microscopy and culture STEC/VTEC serology If patient presents with severe abdominal signs, chest and abdominal X-rays especially erect films looking for signs of perforation must be performed. Abdominal ultrasound is helpful to exclude preceding renal structural abnormalities, pancreatitis and liver involvement. Further imaging including CT abdomen and MRI brain may be required depending on clinical status and neurology. Renal biopsy is very rarely indicated in typical HUS. If performed TMA in more than 50% of glomeruli has the worst prognosis. Renal cortical necrosis is seen if arterial thrombosis is severe. In aHUS, the investigations are slightly more complex and early involvement of tertiary paediatric nephrology services is advised. Specialist investigations will include, complement levels/activity, Factor H concentrations, plasma vWF protease activity, metabolic disease investigations and autoimmune antibody screen. Treatment of aHUS is supportive and includes plasma exchange and early use of a humanized monoclonal antibody that is a terminal complement inhibitor (Eculizumab). The latter treatment has transformed the prognosis of this condition.
List of clinical features associated with HUS System involvement Clinical features Gastrointestinal
Haematology
Renal
Central nervous
Cardiac
Pancreas
Bloody or watery diarrhoea Abdominal cramps Nausea and/or vomiting Rectal prolapse Intussusception Toxic dilatation of colon Bowel perforation Petechiae Mucosal bleeding Jaundice Oliguria or anuria Hypo or hypervolaemia Hypovolaemic shock Hypertension Oedema Lethargy Irritability Seizures Cranial nerve palsy Cerebral oedema Encephalopathy Abnormal posturing Coma Cardiomyopathy Arrhythmias secondary to electrolyte disturbances Myocarditis and tamponade Diabetes mellitus Pancreatitis
Differential diagnosis Thrombotic thrombocytopaenic purpura (TTP) is a condition classified by microangiopathic haemolytic anaemia, thrombocytopaenia, nephropathy, fever and neurological symptoms associated with mutations in the von Willebrand cleaving protease. Other differentials include disseminated intravascular coagulation, sepsis, systemic lupus erythematosus and vasculitis.
Management
Table 2
There is no specific treatment for D þ HUS. Early diagnosis and supportive care is fundamental to clinical recovery. Early involvement of specialist paediatric nephrology advice is also beneficial. These children should be nursed in isolation to prevent secondary transmission. HUS is a notifiable disease and local procedures for contacting Health Protection Agency should be adhered to. Treatment in atypical HUS may include plasmapheresis for complement dysregulation causes and intravenous antibiotics in Streptococcus pneumoniae associated HUS, which in comparison to D þ HUS is not routinely recommended.
Examination should include height, weight and body surface area calculation. Vital signs including blood pressure must be measured. In view of potential complications of HUS, the cardiovascular, respiratory, abdominal, and central nervous systems should be examined, paying particular attention to hydration status and acute abdominal signs. Regular examination during hospital admission is essential.
Investigations Initial inpatient investigations should include the following: FBC and film, assessment of anaemia, thrombocytopaenia and erythrocyte fragmentation Urea and electrolytes Liver and bone function Bicarbonate, assessment of acid-base status Blood glucose and amylase, assess pancreatic involvement Lactate dehydrogenase or haptoglobulin, index of degree of haemolysis Clotting screen Group and save, blood transfusion may be required Urine dipstick for blood and protein Urine microscopy and culture
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General considerations The majority of all children with D þ HUS develop some degree of renal impairment. Approximately two thirds will require renal replacement therapy (RRT e see below). For those children who do not require dialysis, fluid management is key to a successful outcome. Regular assessment of hydration status, twice daily weights, strict fluid balance and regular electrolyte measurements including serum glucose are required. Daily fluid replacement regimen should include insensible losses (400 ml/ m2/day) plus total 24 hour urine output, emphasis is on maintaining euvolaemia in the acute phase. The choice of
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SYMPOSIUM: NEPHROLOGY
intravascular fluid replacement should be governed by plasma electrolytes. Packed red cell transfusion may be required in those with a haemoglobin less than 70 g/l or symptomatic anaemia. Careful monitoring is required in view of potential fluid overload and hyperkalaemia secondary to blood transfusion. Platelet transfusions are generally not required. If the platelet count is particularly low (less than 10 109/l), if there are episodes of active bleeding or pre-operative correction is required then transfusions may be given. Careful monitoring and treatment of hypertension should not be overlooked in the management of these children. In the acute phase, if hypertension persists after fluid overload has been dealt with, antihypertensive therapy should be started with calciumchannel blockers. Once, renal function has improved and if hypertension is persistent, angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) are particularly useful especially if there is also proteinuria. Seizures in central nervous disease should be managed in accordance with advance paediatric life support (APLS) algorithms ensuring that electrolyte, metabolic abnormalities and intracranial lesions have been excluded.
management unless there is evidence of sepsis which must be treated aggressively. Plasma infusions and therapeutic plasma exchange have no proven beneficial role in D þ HUS although there are limited studies to support the use of plasma exchange in D þ HUS with central nervous system involvement. Future treatment options Anti-Shiga toxin antibodies have been shown to prevent HUS in animals. The monoclonal antibodies are intended to neutralize the circulating Stx. When healthy adults have been exposed to monoclonal antibodies, no serious adverse events were reported. In 2003 a randomized, double blind, placebo-controlled study was initiated in Canada and Argentina. Children with STEC positive stools were randomized. Children were treated within 72 hours of the onset of bloody diarrhoea and then followed up for 4 months. The study concentrated on the safety and pharmokinetics of the humanised monoclonal antibody (Urtoazumab) as a therapy against paediatric patients infected with Shiga toxin. The study showed no serious adverse effects of administering the monoclonal antibody and there was no evidence of human antibodies against the monoclonal antibody after treatment. No comment was made on the clinical benefit of administering Urtoazumab in paediatric patients with D þ HUS. Eculizumab is a monoclonal antibody against complement factor 5 and has been used in the recent DþHUS outbreak in Germany with anecdotal reports of benefit. However, a RCT is required to establish its usefulness in this setting.
Renal replacement therapy RRT is required in those children who are fluid overloaded in presence of oliguria, correction of electrolyte or acid-base disturbances and symptomatic uraemia. Common electrolyte disturbance include hyperkalaemia and hyponatraemia. Fluid overload can lead on to pulmonary oedema and myocardial insufficiency. The type of RRT offered is governed by clinical and logistic factors. Peritoneal dialysis (PD) has the advantage of avoiding large volume imbalances. Disadvantages include the need for surgical placement of PD catheter. This may not be possible in view of acute abdominal signs or impede ultrafiltration in during acute enterocolitis. Haemodialysis (HD) has the advantages of potentially being available without the need for abdominal surgery however central venous catheters must be placed in order to perform HD. Disadvantages include the need for anticoagulation, haemodynamic instability and additional loss of blood and platelets in the extracorporeal circulation. Continuous haemofiltration can be instituted in cases of haemodynamic instability.
Prognosis and explanation to patient D þ HUS generally has a good prognosis. Early recognition and treatment including dialysis has improved disease outcomes. Acute mortality rate is 1e4% in D þ HUS. Long term complications after initial disease are seen in approximately 20e40% of patients. Complications include persistent proteinuria (15e30% of cases), arterial hypertension (5e15%), neurological impairment, diabetes mellitus, and chronic renal failure (9e18%). End stage renal failure occurs in 3% of these children. Poor prognostic factors for long term renal complications include; leucocytosis more than 20 109/l with neutrophilia shock during acute illness anuria for more than 5e14 days, more than 10 days worst outcome dialysis for more than 4 weeks is unlikely to lead to full renal recovery hypertension persistent proteinuria central nervous involvement severe colitis and/or rectal prolapse cortical necrosis and TMA (more than 50% glomeruli involved) on renal biopsy atypical HUS It is important to follow up cases of even mild HUS. In a study in which 130 children with D þ HUS not requiring dialysis during the acute illness, 3.8% and 11.5% had proteinuria or hypertension, respectively. Nearly one fifth had microalbuminuria after 12 years from the onset of disease.
Other treatments Nutritional support and early involvement of dietetic support is particularly important to prevent a catabolic state during protracted illnesses. Antimotility agents and nonsteroidal antiinflammatory analgesics (NSAIDs) are not recommended in the management of D þ HUS. Antimotility agents have been associated with higher rates of HUS and NSAIDs increase the risk of gastrointestinal bleeding and reduce renal perfusion thereby affecting GFR. Antibiotics are not recommended as part of the treatment. Experimental data has shown certain classes of antibiotics, trimethoprim, sulfamethoxazole, and quinolones stimulate the bacterial Shiga toxin expression and release. Other studies have shown antibiotic administration does not increase the risk of HUS. In view of the disparity between studies the general consensus is not to administer antibiotics as part of routine
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SYMPOSIUM: NEPHROLOGY
In D HUS, renal prognosis is significantly worse, with nearly half of children developing end-stage renal failure (ESRF) and a quarter dying in the acute period. Renal transplantation in D þ HUS children has low recurrence risk of original illness. In D HUS depending on the aetiology, recurrence of illness in transplanted organ may be extremely high especially in factor deficiencies.
Karpman D, Sartz L, Johnson S. Pathophysiology of typical hemolytic uremic syndrome. Semin Thromb Hemost 2010; 36: 575e85. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 2016; 31: 15e39. Lynn RM, O’Brien SJ, Taylor CM, et al. Childhood hemolytic uremic syndrome, United Kingdom and Ireland. Emerg Infect Dis April 2005; 11: 590e6. Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol July 2010; 5: 1218e28. Rees L, Webb NJA, Brogan PA. Haemolytic uraemic syndrome. Oxford specialist handbooks in paediatrics: paediatric nephrology. Oxford: Oxford University Press, 2007; 384e91. Scheiring J, Andreoli SP, Zimmerhacki LB. Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 2008; 23: 1749e60. Scheiring J, Rosales A, Zimmerhackl LB. Today’s understanding of the haemolytic uraemic syndrome. Eur J Pediatr January 2010; 169: 7e13. Spinale JM, Ruebner RL, Copelovitch L, Kaplan BS. Long term outcomes of Shiga toxin hemolytic uremic syndrome. Pediatr Nephrol 2013; 28: 2097e105. Waters AM, Kerecuk L, Luk D, et al. Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United kingdom experience. J Pediatr August 2007; 151: 140e4. Werber FCD, Cramer JP, ASkar M, et al. Epidermic profile of Shigatoxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med 2011; 365: 1771e80.
Follow up Subsequent medical follow up after the initial admission will depend on the severity of the disease. Those who have had a milder form of HUS should be seen soon after discharge and then annually to monitor for hypertension and proteinuria. This service can be offered by the local paediatrician or general practitioner. Early referral to paediatric nephrologist is recommended should the annual review highlight a concern. Of those children that have had a more protracted illness, they will remain under the care of the paediatric renal services and other specialists depending on the complications of their illness.
Prevention Hygienic measures are the most important factor in preventing the disease. Avoiding ingestion of contaminated food by assuring thorough cooking of meat products, correct pasteurisation of dairy products, and vegetables/fruit to be washed thoroughly. Young children should avoid consumption of unpasteurised food products. It seems extreme to prohibit the petting of farm animals, however hand washing should be encouraged afterwards. Person to person spread amongst children who attend nursery again can be limited by ensuring adequate hand hygiene during toileting. Referral to Health Protection Agency should be done early as soon as diagnosis is suspected. A
Practice points C
FURTHER READING Ariceta G, Besbas N, Johnson S, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol April 2009; 24: 687e96. Bitzan M, Schaefer F, Reymond D. Treatment of typical (enteropathic) hemolytic uremic syndrome. Semin Thromb Hemost September 2010; 36: 594e610. Garg AX, Suri RS, Barrowman N, et al. Long-term renal prognosis of diarrhea-associated haemolytic uremic syndrome. JAMA September 10, 2003; 290: 1360e70. Gianviti A, Tozzi AE, De Petris L. Risk factors for poor renal prognosis in children with hemolytic uremic syndrome. Pediatr Nephrol December 2003; 18: 1229e35. Grisaru S. Management of hemolytic uremic syndrome in children. Int J Nephrol Renov Dis 2014; 7: 231e9. Karpman D. Haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Curr Paediatr 2002; 12: 569e74.
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C
HUS is the combined symptoms of diarrhoea, haemolytic anaemia, thrombocytopaenia and acute kidney injury (AKI). Typical HUS, usually diarrhoea positive D þ HUS (more than 90% of cases), atypical HUS, usually diarrhoea negative D HUS or aHUS (approximately 5% of cases) The D þ HUS is the most common cause of AKI in childhood
Duration of symptoms to recovery is variable, usually occurring 1e3 weeks after onset. Onset of improvement is accompanied by a rise in platelet count. C
C
C
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There is no specific treatment for D þ HUS. Antibiotics can cause the release of toxins hence the use of antibiotics is relatively contraindicated in the treatment of HUS. Renal replacement therapy (RRT) is required in those children who are fluid overloaded in presence of oliguria, correction of electrolyte or acid-base disturbances and symptomatic uraemia Long term complications after initial disease are seen in approximately 20e40% of patients
Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kaur A, Kerecuk L, Haemolytic uraemic syndrome, Paediatrics and Child Health (2016), http://dx.doi.org/ 10.1016/j.paed.2016.04.003