Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children

INTRODUCTION — The hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI) [1]. The most common cause of HUS is due to Shiga toxin-producing Escherichia coli (STEC), and it is one of the main causes of AKI in children under the age of three years.

The treatment and prognosis of STEC-HUS is reviewed here. The clinical manifestations and diagnosis of STEC-HUS are discussed separately. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children".)

DEFINITIONS — Thrombotic microangiopathy (TMA) describes a specific pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis. It includes several primary disorders including thrombotic thrombocytopenic purpura, Shiga toxin-mediated HUS, and complement-mediated HUS or TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Classification — In the past, HUS had been divided into diarrhea-positive and diarrhea-negative HUS. The former, also referred to as typical HUS, primarily resulted from Shiga toxin-producing E. coli (STEC) infections, and less frequently from Shigella dysenteriae type 1 infection. All other causes of HUS were referred to as atypical HUS or assigned to the diarrhea-negative HUS, even though some patients with non-STEC-associated HUS also presented with diarrhea.

However, ongoing research has provided a better understanding of the underlying causes of HUS, especially those due to genetic mutations in the alternative pathway of complement [2,3]. As a result, the following classification has been developed based on pathophysiologic considerations and triggering factors [4]. For this topic, patients identified as either having typical or diarrhea-positive HUS would be diagnosed with acquired HUS due to STEC. In addition, verotoxin, an alternate term for Shiga toxin, has been used extensively in the literature.

●Hereditary causes of TMA/HUS [5]:

•Complement gene mutations

•Inborn errors of cobalamin C metabolism

•Diacylglycerol kinase epsilon (DGKE) gene mutations (see "Overview of hemolytic uremic syndrome in children", section on 'Coagulation pathway')

●Acquired causes of TMA/HUS:

•Infection:

-STEC (see "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children")

-Streptococcus pneumoniae (see "Overview of hemolytic uremic syndrome in children", section on 'Streptococcus pneumoniae')

-Human immunodeficiency virus (HIV) infection

•Autoantibodies to complement factors

•Drug toxicity, particularly in patients with cancer or solid organ transplant recipients

•Rare occurrences in pregnant patients or those with autoimmune disorders (eg, systemic lupus erythematous)

PREVENTION — Prevention of STEC-HUS rests, in part, on measures aimed at reducing the risk of STEC infection. These preventive measures, including public health measures, are discussed in detail elsewhere. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Prevention'.)

Once a patient is infected with STEC, attempts to prevent progression from the bloody diarrheal phase (acute infectious phase) to the postdiarrheal phase of HUS have been largely unsuccessful (eg, antimotility drugs and antibiotics). However, it appears that maintaining adequate hydration may reduce the risk of STEC-HUS.

Hydration — It appears that maintaining adequate hydration may be reduce the risk of STEC-HUS on the hypothesis that kidney hypoperfusion during the STEC infection phase increases the risk of HUS and that volume expansion or maintaining adequate hydration before HUS evolves may diminish its occurrence or severity.

A systematic review of the literature, which included both randomized trials and observational studies, provided evidence supporting the benefit of vigorous fluid repletion during the diarrheal phase of STEC infection to prevent or reduce the severity of HUS [6]. In this review, elevated hematocrit (measure of inadequate hydration) was associated with oligoanuria (odds ratio [OR] 2.38, 95% CI 1.30-4.35), kidney replacement therapy (OR 1.90, 95% CI 1.25-2.90), and death (OR 5.13, 95% CI, 1.50-17.57), whereas administration of intravenous (IV) fluids up to the day of HUS diagnosis was associated with a decreased risk of kidney replacement therapy (OR 0.26, 95% CI, 0.11-0.60). Mortality was increased for clinically dehydrated patients compared with hydrated patients (OR 3.71, 95% CI 1.25-11.03).

In a subsequent large retrospective study of children with STEC, risk factors based on multivariate analysis for HUS included young age, elevation of hematocrit, platelet count and serum creatinine, low serum sodium, and administration of IV fluid ≥4 days following diarrhea onset [7]. In addition, a small study reported that volume expansion with normal saline given to 16 patients improved outcome compared with 19 historical controls [8]. Indirect data suggest that increased hemoconcentration was associated with more severe HUS [9].

Although these data suggest an association between volume depletion and adverse outcomes related to STEC-HUS, no studies directly evaluated the effect of hydration during STEC infections on the risk of developing HUS. Nevertheless, these limited data suggest that early parenteral volume expansion with isotonic IV solutions during STEC infections for patients who are volume depleted is associated with attenuated acute kidney injury (AKI). Further research is needed to unequivocally determine whether volume expansion can reduce the risk of HUS or its severity. In addition, there is evidence that suggests a need to maintain adequate hydration during the acute phase of HUS, which is discussed below. (See 'Fluid management' below.)

Inconclusive or failed measures — The challenge of identifying any preventative treatments for STEC-HUS was illustrated by a review of the literature that found four small trials that investigated four different interventions (antibiotics [trimethoprim‐sulfamethoxazole], anti-Shiga toxin antibody-containing bovine colostrum, Shiga toxin-binding agent, and a monoclonal antibody against Shiga toxin [urtoxazumab]) [10]. However, there was no conclusion regarding effectiveness or risks, because of the small number of trials that included small sample sizes.

●Antibiotics – For patients with STEC, the impact of antibiotic administration during the bloody diarrheal phase remains uncertain and may be dependent on the infecting STEC genotype and the choice of antibiotic agent [11]. Limited animal data suggest that different antibiotic agents have varying effects on the production of the Shigatoxin 2 (Stx2, which is associated with HUS) and Shigatoxin 1 (Stx1) in specific STEC genotypes [12]. There are clinical observational data that suggest administration of beta-lactams and trimethoprim/sulfamethoxazole is associated with increased risk of developing HUS [13,14], whereas fluoroquinolones and fosfomycin therapy may be beneficial in reducing subsequent HUS cases when outbreaks occur with specific amenable STEC genotypes [11,15-17]. However, the quality of the evidence is poor and case definition and interventions vary widely amongst studies. As a result, avoidance of prophylactic antibiotic remains the prudent course until there are conclusive data that determine which antibiotic therapy is beneficial and when it should be applied based on the ability to quickly identify the amenable clinical circumstances (ie, identification of the STEC strain). (See "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment", section on 'Antibiotics'.)

Antimicrobial therapy does not appear to increase the risk of S. dysenteriae type 1-associated HUS [18]. (See "Shigella infection: Epidemiology, clinical manifestations, and diagnosis", section on 'Hemolytic-uremic syndrome (HUS)'.)

●Antimotility drugs – Antimotility drugs (such as anticholinergic agents and narcotics) do not reduce the progression to HUS due to STEC infections but, in fact, appear to increase the risk of subsequent development of STEC-HUS and should not be given to patients with confirmed or suspected infections due to STEC. In one retrospective review of 278 children with HUS, the use of antimotility drugs (anticholinergic agents and narcotics) was associated with an increased risk of subsequent development of HUS (OR 2.9, 95% CI 1.2-7.5) [19]. In another retrospective study of 91 patients, antimotility drugs (anticholinergic agents and narcotics) increased the risk of central nervous system (CNS) dysfunction (OR 8.5, 95% CI 1.7-42.8) [20]. There was no difference in the duration of diarrhea between patients who received antimotility drugs and those who did not.

MANAGEMENT OVERVIEW — The management of STEC-HUS is primarily based on supportive care because there is no proven safe and beneficial specific therapeutic intervention (see 'Supportive therapy' below). However, eculizumab and/or plasma therapy may be considered in patients with severe central nervous system (CNS) involvement (eg, seizures or coma) who have a poor prognosis. (See 'Directed interventions for serious CNS involvement' below.)

SUPPORTIVE THERAPY

Overview — The prognosis of HUS has improved, in part because of the early institution of supportive therapy and improvements in intensive care and kidney replacement therapy. Appropriate care should be given for the following:

●Anemia

●Thrombocytopenia

●Fluid and electrolyte disturbances

●Acute kidney injury (AKI)

●Hypertension

●Neurologic dysfunction

●Other organ involvement including colon, heart, pancreas, and lung

Anemia — Patients with HUS can become profoundly and rapidly anemic. Based on clinical experience, packed red blood cells should be transfused when the hemoglobin (Hgb) level is <6 g/dL or hematocrit <18 percent to avoid cardiovascular and pulmonary compromise. Approximately 80 percent of children with STEC-HUS require red blood cell transfusions [21]. (See "Red blood cell transfusion in infants and children: Indications".)

A post-transfusion goal of an Hgb level between 8 and 9 g/dL is recommended to prevent cardiac and pulmonary complications resulting from high output cardiac failure. The goal is not to restore the Hgb level to normal, because the increased volume may cause heart failure, pulmonary edema, and hypertension [22].

Because of the concerns of hypervolemia, clinically indicated transfusions should be given slowly and cautiously with frequent monitoring of the patient's vital signs [23]. In our practice, we typically administer packed red blood cells at a total volume of 10 mL/kg over three to four hours, which typically raises the Hgb level by 1 g/dL. Transfusions should be stopped if the vital signs suggest cardiopulmonary vascular overload (eg, hypertension, tachycardia, and/or tachypnea). In addition, serum or plasma potassium should be closely monitored due to the risk of hyperkalemia for patients with acute kidney injury. Blood products should be volume-reduced and preferably depleted of leukocytes and platelets to avoid alloimmunization (thus reducing the risk of graft rejection in patients who may subsequently require kidney transplantation). If the patient is undergoing hemodialysis, transfusions should be given during dialysis to minimize the risks of hypervolemia and hyperkalemia. (See "Red blood cell transfusion in infants and children: Administration and complications", section on 'Administration' and "Red blood cell transfusion in infants and children: Selection of blood products", section on 'Leukoreduced red blood cells'.)

Most patients do not require iron therapy, as iron from hemolyzed blood is available for erythropoiesis. In addition, there is no indication for the routine use of erythropoietin.

Thrombocytopenia — Platelet transfusion is reserved for patients with HUS who have significant clinical bleeding or if an invasive procedure is required [23]. In our practice, we limit platelet transfusions to patients with active bleeding.

Platelet transfusions are uncommon, as clinically significant bleeding is infrequent because the platelet count rarely falls below 10,000/mm³, and platelet production and function are normal. In one retrospective study, there were no bleeding complications in 73 patients who required an invasive procedure (ie, peritoneal dialysis catheter or central venous catheter placement) [24]. In this cohort, the mean platelet counts were 37,600/mm³ in patients who received platelet transfusions and 64,800/mm³ in those not receiving transfusions.

Although there has been a theoretical concern that platelet transfusion contributes to new or expanding thrombi due to consumption of infused platelets, as reported in adults with thrombotic thrombocytopenic purpura [25,26], limited data in children suggest that platelet transfusion does not exacerbate the course of the disease [27]. However, platelet transfusion may induce anti-human leukocyte antigen (HLA) antibodies, which may be deleterious later if the patient progresses to end-stage kidney failure and undergoes kidney transplantation.

Fluid and electrolyte management

Fluid management — The standard fluid management of patients with HUS has been based on careful assessment since competing processes can lead to either decreased or increased intravascular volume [23]. Decreased volume may result from vomiting, decreased oral intake, or diarrhea, while increased intravascular volume may arise from oliguria or anuria. As a result, fluid management is based on the intravascular fluid status of the patient and kidney function. Patients with decreased intravascular volume are repleted to a euvolemic state, whereas those with increased intravascular volume and diminished urine output are fluid restricted. Patients with increased intravascular volume may require dialysis treatment to remove fluid, especially if there is cardiac and pulmonary compromise. Once the patient is in a euvolemic state, administration of fluids should be given as insensible losses plus urine output until kidney function returns to normal.

However, observational studies have reported volume expansion may reduce the risk of kidney replacement therapy (KRT):

●An Italian study from 2012 and 2014 reported, early volume expansion targeted to increase body weight by 10 percent improved outcome for 38 children with STEC-HUS compared to historical controls from 2006 to 2009 [28]. In this study, patients with intravenous (IV) fluid infusion resulting in a mean increase in body weight of 12.5 percent after 48 hours of hospitalization had a lower rate of KRT (26 versus 58 percent), shorter hospital course (9 versus 12 days), and shorter duration of intensive care (2 versus 9 days) compared with the historical control group. There was a trend for a lower risk of central nervous system (CNS) involvement with early volume expansion (8 versus 24 percent), although this was not statistically significant. In the volume expansion group, there were no serious adverse effects. One patient had evidence of fluid overload (eg, hypertension) that responded to diuretic (eg, furosemide) therapy.

●A second Italian study reported that 16 children with STEC-HUS treated with volume expansion had a lower risk of KRT compared with historical control who did not receive volume expansion [8].

Although these results are encouraging, it should be noted that there is a concern for potential bias with the use of historical controls with potential difference in severity of disease and treatment, and the relatively small number of patients. Nevertheless, these findings should prompt further investigations to confirm the potential benefit of early volume expansion in all children with STEC-HUS.

Based on these results, we agree that fluid management should be directed to rapidly correct any evidence of volume depletion, which is most likely the more common fluid state of patients with STEC-HUS. However, until further evidence is provided, we do not recommend routine volume expansion without proper assessment of intravascular volume status and kidney function, especially if there is evidence of increased intravascular volume. Frequent monitoring of fluid balance, weight, and vital signs remains imperative throughout the course of the acute process. At the first sign of hypertension or cardiopulmonary overload, fluids should be restricted. Diuretics rarely avert anuria, but a trial of furosemide (2 to 5 mg/kg per dose) may be attempted to induce a diuresis, particularly in patients with cardiopulmonary overload. Diuretics should not be continued in the patient who fails to respond. Dialysis therapy is required if fluid restriction and/or diuretic therapy fail to improve the compromised cardiorespiratory status of the patient in a timely manner. (See "Prevention and management of acute kidney injury (acute renal failure) in children" and 'Dialysis' below.)

Electrolyte management — Electrolyte disturbances are common, usually due to acute kidney function impairment or kidney failure. They include hyperkalemia, hyperphosphatemia, and metabolic acidosis. Management of these disorders is the same as in patients with other causes of AKI and is discussed elsewhere. (See "Prevention and management of acute kidney injury (acute renal failure) in children", section on 'Electrolyte management'.)

Acute kidney injury — In patients with HUS who develop kidney function impairment or kidney failure, nephrotoxic medications should be stopped. The dosing of drugs that are excreted by the kidney also must be readjusted for kidney dysfunction. (See "Prevention and management of acute kidney injury (acute renal failure) in children", section on 'Drug management'.)

Dialysis — There is no evidence that early dialysis affects clinical outcome. As a result, the indications for dialysis in children with HUS are similar to those in children with other forms of AKI. These include the following:

●Signs and symptoms of uremia

●Azotemia defined as blood urea nitrogen ≥80 to 100 mg/dL (29 to 36 mmol/L)

●Severe fluid overload (eg, cardiopulmonary compromise and/or hypertension) that is refractory to medical therapy

●Severe electrolyte abnormalities (eg, hyperkalemia and acidosis) that are refractory to medical therapy

●Need for nutritional support in a child with oliguria or anuria

(See "Pediatric acute kidney injury (AKI): Indications, timing, and choice of modality for kidney replacement therapy (KRT)", section on 'Indication and timing for KRT'.)

The choice of kidney replacement modalities varies among pediatric nephrologists and medical centers. In most young children, peritoneal dialysis is selected [29]. However, there is no evidence of increased benefit of peritoneal dialysis compared with hemodialysis. If there is a severe abdominal complication requiring surgical intervention, peritoneal dialysis is contraindicated. In our center, IV antibiotic prophylaxis is administered prior to PD catheter placement to reduce the risk of peritonitis [29].

Hypertension — In patients with HUS, hypertension is caused by overexpansion of intravascular volume and/or ischemia-induced activation of the renin-angiotensin system [30]. Management is directed toward correcting the fluid status and the use of antihypertensive agents. (See 'Fluid management' above.)

We suggest the use of calcium channel blockers (such as nifedipine or nicardipine) as the initial choice of antihypertensive agents for this disease because of the concern of reduced kidney perfusion with angiotensin-converting enzyme (ACE) inhibitors (table 1) [23]. In contrast, there are proponents for the use of ACE inhibitors for its potential renoprotective effect in children with long-term sequelae of HUS (eg, proteinuria, kidney function impairment, and hypertension) [31,32].

After the acute phase of HUS, we suggest that antihypertensive therapy be changed to ACE inhibitors in patients who appear to have long-term kidney sequelae. Long-term ACE inhibitor therapy may be beneficial as it reduces protein excretion, which may retard chronic kidney disease (CKD) progression as well as lower blood pressure in hypertensive patients. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of antihypertensive drugs on proteinuria' and "Chronic kidney disease in children: Complications", section on 'Hypertension'.)

Neurologic dysfunction — Serious complications of the CNS, such as seizures, strokes, and decreased level of consciousness occurring in 10 percent of cases are predictors of poor outcome [33]. In any patient with HUS who presents with serious neurologic dysfunction (eg, seizure and coma), radiologic imaging should be performed to assess and confirm CNS involvement. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children", section on 'Other organ involvement'.)

Management issues regarding children with CNS involvement include the following:

●Eculizumab therapy appears to improve neurologic outcome and is our preferred therapy in patients with severe CNS involvement. (See 'Eculizumab' below.)

●The benefit of plasma therapy remains unproven in patients with STEC-HUS. Although it is often used in patients with severe CNS involvement (eg, seizure or stroke), we do not routinely provide plasma therapy in this clinical setting. Plasma therapy is often beneficial in patients with complement-mediated HUS. (See 'Plasma infusion and plasma exchange' below and "Complement-mediated hemolytic uremic syndrome in children", section on 'Plasma therapy'.)

●Severe hypertension may be a contributing factor for CNS involvement. In these patients, control of significantly elevated blood pressure will result in resolution of some of the CNS manifestations.

●Seizures are treated with parenteral antiepileptic agents. These include diazepam, phenytoin, and fos-phenytoin. Seizures also may be secondary to severe hypertension, which become refractory without appropriate blood pressure control. (See "Management of convulsive status epilepticus in children".)

Other organ involvement — Although not as common as kidney and neurologic complications, patients may develop severe gastrointestinal complications, cardiac dysfunction, and pancreatitis [21,34]. In addition, respiratory complications secondary to increased intravascular volume may occur. Management for these potential complications includes the following:

●Gastrointestinal complications – Severe colitis may progress to necrosis and in some cases intestinal perforation. Management includes serial abdominal examinations, guaiac testing of the stool, and the use of parenteral nutrition. Surgical intervention may be required.

●Cardiac dysfunction – Cardiac dysfunction can be a result of cardiac ischemia and fluid overload. Pericarditis may be associated with uremia. Appropriate therapy should be directed to the underlying pathology and may include inotropic agents, fluid restriction, and/or dialysis. Measurement of troponin levels may be useful to detect myocardial ischemia.

●Pancreatitis – Clinically significant pancreatitis can occur resulting in insulin deficiency. Insulin therapy may be required for hyperglycemia. (See "Management of acute pancreatitis".)

●Pulmonary complications – Pulmonary edema and effusions may result from intravascular fluid overload. Management may include fluid restriction, diuretics, dialysis, and/or ventilatory support.

DIRECTED INTERVENTIONS FOR SERIOUS CNS INVOLVEMENT

Overview — Multiple modalities and/or agents have been utilized that are directed against the underlying or presumed pathogenic mechanisms of STEC-HUS. These include antithrombotic agents, plasma exchange and/or plasma infusion, tissue-type plasminogen activator, and oral Shiga toxin-binding agent.

Although none of these agents have been shown to be efficacious, there may be a role for eculizumab (a monoclonal antibody that blocks complement activity by cleavage of C5) and plasma infusion/exchange in patients with serious central nervous system (CNS; seizures, strokes, and decreased level of consciousness) involvement. In our center, we prefer the use of eculizumab, however, this medication is expensive and may not be universally available. The remaining agents are not recommended.

Eculizumab — Eculizumab, a monoclonal antibody to complement factor C5 that blocks complement activation, has been used in the treatment of patients with complement-mediated HUS. Although data are inconclusive regarding effectiveness [35-39], we administer eculizumab to patients with STEC-HUS and severe CNS involvement (eg, seizures, coma, neurologic defect) because these patients are at significant risk for death and long-term morbidity. A "neurologic score" has been proposed to guide when eculizumab should be used to treat CNS complications [37]. However, further study is needed to validate its clinical use.

We also consider eculizumab in cases of other severe organ involvement, such as cardiac dysfunction. However, this medication is costly and so may not be available because of the prohibitive cost. (See 'Prognosis' below.)

Eculizumab is beneficial in treating patients with complement-mediated HUS (see "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement blockade (eculizumab)'). Several small case series have also shown that eculizumab may be beneficial in patients with STEC-HUS and CNS involvement [37,40-43]. In contrast, no benefit was seen with the administration of eculizumab over standard care for patients treated in the 2011 outbreak of E. coli O104:H4 [44-46]. However, the administration of eculizumab was often delayed after plasma exchange.

In a randomized trial involving 100 children with STEC-HUS, eculizumab did not appear to be associated with improved renal outcome during the acute phase, but the proportion of patients experiencing renal sequelae at one year was lower in the eculizumab group than in the placebo group (43.48 and 64.44 percent, respectively) [47].

Additional support for the use of eculizumab is provided by the in-vitro demonstration that complement activation occurs in STEC-HUS [48-52]. It has also been shown that Shiga toxin directly activates complement via the alternative pathway through its binding to complement factor H and complement factor H-related protein [53,54]. These findings provide a rationale for the use of eculizumab with evidence that complement activation contributes to the inflammatory and prothrombotic mechanisms that are involved in the pathogenesis of STEC-HUS.

Dosing — The dosing of eculizumab is based on a regimen used in a clinical trial for eculizumab treatment in patients with complement-mediated HUS. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement blockade (eculizumab)'.)

The following is the initial dosing of eculizumab to treat STEC-HUS, which is dependent on patient's body weight:

●5 to <10 kg – 300 mg

●10 to <40 kg – 600 mg

●≥40 kg – 900 mg

We usually administer a second dose at day 7 after the first dose. The decision for additional doses of eculizumab is dependent on the clinical status of the patient. We consider additional doses if the neurologic status has not normalized and/or if kidney function has not improved. If plasmapheresis therapy is also being performed, a repeat dose is given after each plasmapheresis session.

Adverse effect — Treatment with eculizumab is associated with potentially life-threatening risk of encapsulated bacterial infection (Neisseria meningitidis, S. pneumoniae, Haemophilus influenzae) as a result of terminal complement blockade. Therefore, children must receive meningococcal vaccination (both ACYW and serogroup B) before being treated with eculizumab as well as vaccination against H. influenzae and S. pneumoniae. Antibiotic prophylaxis is also recommended during complement blockade during the duration of eculizumab therapy. Antimicrobial prophylaxis for prevention of meningococcal infection consists of penicillin, dosage for patients ≥3 years of age of 250 mg orally twice a day and for children <3 years of age 125 mg orally twice daily. In the presence of penicillin allergy, a macrolide can be substituted. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving C5 inhibitors'.)

Plasma infusion and plasma exchange — Plasma exchange has often been used in children with STEC-HUS and severe CNS involvement (eg, stroke) based on reported benefits of plasma exchange in adults with TTP and severe neurologic dysfunction. However, there is no evidence that it is beneficial in the treatment of STEC-HUS. As a result, we do not routinely administer plasma therapy as the initial treatment for patients with severe CNS involvement. In our center, eculizumab is the preferred initial intervention. If plasma exchange is performed, the volume of exchange is 40 to 60 mL/kg and fresh frozen plasma is generally used as the replacement fluid. (See "Immune TTP: Initial treatment" and "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology" and "Complement-mediated hemolytic uremic syndrome in children", section on 'Plasma therapy'.)

There are no randomized controlled studies that evaluate the efficacy of plasma exchange in children with STEC-HUS. Information is based on observational data:

●During the 2011 E. coli O104:H4 outbreak in Germany, a benefit from plasma exchanges used alone or with steroids could not be demonstrated [44]. During the same outbreak, five adult patients in southern Denmark were treated with daily plasma exchange early after onset and all had favorable outcome with normal neurologic status [55]. Although a long-term follow-up study found an association between the use of plasma therapy during the acute phase and poor long-term outcome, it should be noted that plasma therapy was used more frequently in severe cases [56].

●In an earlier meta-analysis that evaluated plasma exchange from four observational studies, there was no clinical benefit seen with plasma exchange in patients with STEC-HUS [57]. However, the small number of studies that are observational in their design and the variability of the clinical spectrum of disease hamper the analysis.

Not recommended therapies

Antithrombotic agents — The rationale for the use of antithrombotic agents in HUS was based on the histologic evidence of thrombus formation. It is important to remember, however, that this disorder is primarily characterized by platelet rather than fibrin consumption. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children".)

Two prospective controlled trials have compared combinations of antithrombotic agents (eg, either urokinase and heparin or dipyridamole and heparin) with supportive care or supportive care alone [58,59]. The duration of kidney failure, hemolysis, and thrombocytopenia, and the long-term outcome were all similar in both control and treated groups. Furthermore, hemorrhagic complications were more common in the treated patients [58].

As a result, we do not recommend antithrombotic agents in patients with STEC-HUS, because there is no evidence of clinical benefit and there is an increased risk of hemorrhagic complications.

Oral Shiga toxin-binding agent — In a placebo-controlled randomized study of 145 children diagnosed with HUS, Synsorb-Pk, an oral agent that binds Shiga toxin, did not improve clinical outcome [60]. The incidence of death or serious extrarenal events was the same in the treated and placebo control groups (18 and 20 percent, respectively). As a result, we do not recommend the use of oral Shiga toxin-binding agents.

Tissue-type plasminogen activator — It has been suggested that plasminogen activator inhibitor type 1 (PAI-1) may be a circulating inhibitor of fibrinolysis in HUS. In one report, for example, normalization of plasma PAI-1 levels correlated with improvement in kidney function [61]. One case report described a successful response to alteplase (recombinant tissue-type plasminogen activator) [62]. However, these are single case reports and we do not recommend the use of PAI-1 except in a research setting.

PROGNOSIS — The hematologic manifestations of STEC-HUS completely resolve usually within one to two weeks. The prognosis for recovery of kidney function is generally favorable, with resolution beginning after hematologic improvement, but up to one-third of patients develop mild kidney dysfunction in long-term follow-up (see 'Long-term outcome' below). The mortality rate is less than 5 percent [63-66], but another 5 percent of patients have significant sequelae (eg, stroke or kidney failure) [63]. Long-term outcome results generally are from data of patients with E. coli 0157:H7-associated HUS, although a similar favorable outcome has been observed in children who were affected during the large German HUS outbreak in 2011 due to E. coli O104:H4 [67]. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children", section on 'E. coli strains'.)

Acute mortality — Mortality typically occurs acutely during the initial hospitalization with reported rates of approximately 3 to 4 percent [66,68]. Causes of death during the acute phase of HUS include central nervous system (CNS) injury (eg, cerebral edema, cerebral infarction, or brain death), hyperkalemia, coagulopathy, sepsis, heart failure, pulmonary hemorrhage, and injury to the gastrointestinal tract [66,69].

Reported factors associated with mortality include elevated white blood count, hematocrit greater than 20 percent, an episode of respiratory tract infection, particularly pneumonia due to S. pneumoniae, and hyponatremia [66,68]. In a large retrospective study, all patients without bloody stools survived [66].

Long-term outcome — Approximately 60 to 70 percent of patients recover completely from the acute phase of STEC-HUS [67,70]. In the remaining patients, there is a varying degree of the severity of sequelae, which are primarily due to initial kidney injury.

●Risk factors – Children who have long-term complications from HUS often have one or more of the following risk factors during the acute phase of the disease [63-65,70,71]:

•A WBC >20,000 per mm³ at presentation. The leukocytosis in part reflects neutrophil activation resulting from monocyte release of the neutrophil chemoattractant interleukin-8; these neutrophils may then contribute to tissue damage [72].

•Initial oliguria/anuria that is persistent (>5 days of anuria and >10 days of oliguria) and prolonged dialysis [70,73].

•Kidney histology showing a glomerular microangiopathy affecting >50 percent of glomeruli, arterial microangiopathy, and/or cortical necrosis.

●Kidney outcomes – Although the glomerular filtration rate (GFR) returns to normal in most children with STEC-HUS, follow-up after the acute phase reveals evidence of irreversible kidney injury in 30 to 50 percent of children, including the following findings [64,65,67,70,71,74,75]:

•Hypertension

•Mild proteinuria (usually less than 1000 mg per day)

•Subclinical decline in GFR with plasma creatinine concentration remaining in the normal range

•Chronic kidney disease (CKD) and ESKD

Long-term outcomes were illustrated in a report of 122 children with STEC-HUS who did not require dialysis, with median follow-up of 11.3 years [75]. At last follow-up (median duration of 11.3 years), 67 percent had complete recovery of kidney function, 30 percent had stage 1 CKD, 3 percent had stage 2 CKD, and none had more advanced stages or kidney failure. One-half of the CKD developed within five years of STEC-HUS. A separate report that included children who required dialysis in the acute phase of STEC-HUS found that 28 percent (19/69) had proteinuria and 19 percent (14/72) were hypertensive after a median follow-up of three years [67]. However, only two patients had ESRD: one who never recovered kidney function, and the other who was initially dialyzed and recovered during the acute phase but had deterioration of renal function after 19 months resulting in reinitiation of dialysis after 44 weeks. One other patient had impaired kidney function with an estimated GFR of 53 mL/min per 1.73 m².

Thus, a normal GFR at late follow-up does not necessarily imply complete recovery of kidney function [76]. Some patients with a normal serum creatinine have a persistent reduction in kidney blood flow and a lower-than-normal maximum GFR after a protein load [77,78]. These findings suggest permanent nephron loss, with compensatory hyperfiltration in the surviving nephrons, which maintains the total filtration rate. Sequential kidney biopsies may show glomerular scarring, which could reflect secondary hemodynamically-mediated glomerular injury resulting from the initial nephron loss [77] In addition, endothelial dysfunction may be observed during long-term follow-up in some children with STEC-HUS despite normal kidney function and blood pressure [79]. (See "Secondary factors and progression of chronic kidney disease".)

●Recurrence after kidney transplantation – In patients with STEC-HUS who progress to kidney failure and undergo renal transplantation, recurrence of HUS in the transplanted kidney is rare (0 to 10 percent) [77,80-85]. In one review of 118 children, there was only one case of recurrence with allograft loss (0.8 percent) [85]. Because it is rare that HUS recurs in normal patients, if there is a recurrence after renal transplantation, an evaluation for an underlying mutation resulting in complement-mediated HUS should be performed [5]. (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Genetic variants'.)

In general, allograft survival in patients with STEC-HUS is similar to survival in those with other causes of CKD [81]. However, the diagnosis of recurrence of HUS after kidney transplantation may be difficult. Although cyclosporine and other calcineurin inhibitors have no detrimental effect on recurrence, these immunosuppressive agents may cause a nephropathy that has many features in common with HUS. In addition, it may be difficult to distinguish recurrence of HUS from severe acute vascular or chronic rejection on a kidney biopsy. (See "Overview of hemolytic uremic syndrome in children", section on 'Acquired non-infectious causes' and "Cyclosporine and tacrolimus nephrotoxicity".)

FOLLOW-UP — Based on the risks for progressive CKD described above [70,75,86], patients with STEC-HUS should have yearly follow-up to monitor for signs of hypertension, proteinuria, and kidney function impairment, with ongoing monitoring during adulthood . Each visit should include blood pressure measurement and laboratory evaluation of kidney function including urinalysis and serum creatinine concentration. For patients who become pregnant, it is also recommended that follow-up care includes assessment for elevated blood pressure and proteinuria.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hemolytic uremic syndrome in children" and "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)

SUMMARY AND RECOMMENDATIONS — The hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). The most common cause of HUS is due to Shiga toxin-producing Escherichia coli (STEC).

Prevention of hemolytic uremic syndrome

●The prevention of STEC-HUS is dependent on measures that decrease the risk of infection. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Prevention'.)

●There is no known effective therapy to prevent progression from the bloody diarrheal phase (acute infectious phase) to the postdiarrheal phase of HUS.

●In patients with confirmed or suspected infections due to enterohemorrhagic E. coli, we recommend antibiotics and antimotility agents not be given (Grade 1C). (See 'Prevention' above.)

●We suggest that adequate hydration be maintained, including the use of early parenteral fluid for children during the diarrheal phase of STEC infection to avoid kidney hypoperfusion (Grade 2B).

Management of acute phase — Therapy for STEC-HUS is supportive and includes the following (see 'Supportive therapy' above):

●Patients with HUS can become profoundly and rapidly anemic and require red blood cell transfusions. In our clinical experience, we transfuse when the hemoglobin level falls below 6 g/dL. (See 'Anemia' above.)

●We suggest platelet transfusion only if there is active bleeding (Grade 2C). (See 'Thrombocytopenia' above.)

●For each patient, the fluid status is assessed and management is directed toward returning the patient to a euvolemic state. In particular, management should be directed to rapidly correct any evidence of volume depletion. Fluids are then administered as insensible losses plus urine output until kidney function returns to normal. Frequent monitoring of fluid balance, weight, and vital signs is required to detect early signs of fluid overload. If this occurs, prompt fluid restriction is begun. (See 'Fluid management' above.)

●Initial assessment and monitoring are required to detect hyperkalemia, hyperphosphatemia, and metabolic acidosis. Management of these disorders is the same as in patients with other causes of AKI. (See "Prevention and management of acute kidney injury (acute renal failure) in children", section on 'Electrolyte management'.)

●Dialysis therapy is initiated as indicated for AKI. (See "Prevention and management of acute kidney injury (acute renal failure) in children", section on 'Kidney replacement therapy' and "Pediatric acute kidney injury (AKI): Indications, timing, and choice of modality for kidney replacement therapy (KRT)".)

●Hypertension is managed by fluid restriction, antihypertensive agents, and dialysis if needed. We suggest the use of calcium channel blockers (such as nifedipine or nicardipine) as the initial choice of antihypertensive agents in the acute phase of the illness (Grade 2C). (See 'Hypertension' above.)

●Parenteral antiepileptic agents (eg, diazepam, phenytoin, and fos-phenytoin) are used in the management of seizures in patients with HUS. (See "Management of convulsive status epilepticus in children".)

●In patients with severe neurologic involvement, we suggest administering eculizumab, a monoclonal antibody to complement factor C5 that blocks complement activation (Grade 2C). (See 'Eculizumab' above.)

●We do not recommend the use of antithrombotic agents or oral Shiga toxin-binding agent (Grade 1B). (See 'Directed interventions for serious CNS involvement' above.)

Prognosis and follow-up

●In general, the short-term prognosis is favorable, with mortality rates below 5 percent. However, up to one-third of patients eventually develop chronic kidney disease (CKD) over the subsequent two decades and the risk of developing renal failure is not negligible. In patients who require kidney transplantation, recurrence of HUS is rare. (See 'Prognosis' above.)

●Annual follow-up of patients with HUS should include blood pressure measurement, urinalysis, and serum creatinine. (See 'Follow-up' above.)

●After the acute phase of HUS, we suggest that angiotensin-converting enzyme (ACE) inhibitors be given to patients with chronic hypertension or other kidney sequelae (Grade 2C). (See 'Hypertension' above.)