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

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

The clinical manifestations and diagnosis of HUS due to STEC (STEC-HUS) in children are presented in this topic review. The treatment and prognosis of this disorder and other causes of HUS in children are presented separately. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children" and "Overview of hemolytic uremic syndrome in children" and "Complement-mediated hemolytic uremic syndrome in children".)

STEC-HUS in adults is discussed separately. (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Causes of ST-HUS'.)

CLASSIFICATION — In the past, HUS had been divided into diarrhea-positive and diarrhea-negative HUS. Diarrhea-positive HUS, also referred to as typical HUS, primarily resulted from 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. Studies on interventions in patients with STEC-HUS may have used the earlier nomenclature of diarrhea-positive or -negative HUS, or typical versus atypical HUS. In addition, verotoxin, an alternate term for Shiga toxin, has been used extensively in the literature.

For this topic, we use the current classification system. Thus, patients identified as having either typical or diarrhea-positive HUS would be classified as having acquired HUS due to STEC (STEC-HUS). This classification is based on pathophysiological considerations and triggering factors [2], and it is also based largely on research that has provided a better understanding of the underlying causes of HUS, especially those due to genetic mutations in the alternative pathway of complement [3-5]. Classification is discussed in more detail separately. (See "Overview of hemolytic uremic syndrome in children", section on 'Classification'.)

MICROBIOLOGY — STEC-HUS occurs after an infection with Shiga toxin-producing enterohemorrhagic E. coli (STEC) and accounts for almost all the cases of post-diarrheal HUS in the United States [6-9]. In a review of the literature, the risk of developing HUS for patients with acute illness was approximately 0.1 percent, but the risk is greater in children four years and younger [10].

Escherichia coli strains — Different E. coli strains have been associated with both sporadic and epidemic STEC-HUS cases throughout the world. Due to the changes observed in the epidemiology of STEC serotypes, microbiological diagnosis needs to be focused on the virulence factors in stools and diagnosis of the individual E. coli strains. STEC fall into two clinically relevant categories: those that contain a gene encoding Shiga toxin 2 (Stx2; with or without a gene encoding Shiga toxin 1 [Stx1]) and those that do not (ie, their only Shiga toxin gene encodes Stx1) (table 1). Stx2 production is associated with HUS [11-13]. In a prospective multicenter study of 4767 children with bloody diarrhea, 34 of 214 with identified STEC infection developed HUS [12,14]. In this cohort of STEC-infected children, the risk of HUS was 0, 24, and 13 percent for STEC gene expression for only Stx1, only Stx2, and both Stx1 and Stx2, respectively.

The microbiology and diagnoses of STEC infections are discussed separately [15,16]. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Microbiology' and "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment", section on 'Microbiologic diagnosis'.)

The E. coli serotype associated with HUS varies regionally and over time. In much of the world, including the United States, Europe, and Latin America, E. coli 0157:H7 has been the most frequent strain associated with HUS in children [4,11,17,18]. Almost all E. coli O157:H7 contain a gene encoding Stx2.

However, other strains have become more common including O26, O80, O91, O111, O103, O104, O121, and O145, [4,19-23]. A large outbreak of STEC-HUS in Germany was caused by E. coli O104:H4 [24-26]. In Australia, approximately one-half of cases of post-diarrheal HUS are due to E. coli 0111 [27,28]. In addition, there was an outbreak of E. coli 0111 infections in the United States, in which 26 of 156 patients developed HUS [29].

PATHOGENESIS — Shiga toxin-mediated injury to vascular endothelial cells in the kidney, brain, and other organs underlies the pathogenesis of STEC-HUS. These potent cytotoxins are released by bacteria in the gut, then enter the bloodstream and cause endothelial injury by binding to the globotriaosylceramide (Gb3) receptor on the plasma membrane of endothelial cells, podocytes, and proximal tubular cells [30]. Shiga toxin binding to endothelial cells activates complement and platelet thrombus formation on the endothelial cells, leukocyte binding to the endothelial cells, and induces apoptosis. In addition, these endothelial cells become thrombogenic, which initiates microvascular thrombus formation [31]. The pathogenesis of STEC is discussed in more detail separately. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Pathogenesis'.)

EPIDEMIOLOGY

Incidence — STEC-HUS accounts for over 90 percent of cases of HUS in children. It principally affects children under the age of five years [4]. In addition, HUS complicates 6 to 9 percent of STEC infections. The reported annual incidence in Europe and North America is 0.5 to 0.8 cases per 100,000 children between 15 and 18 years of age and 1.9 to 2.9 cases per 100,000 children 3 to 5 years of age [4,11,32]. The incidence of STEC-HUS in Latin America remains 10 times higher than in other continents (10 to 17 cases per 100,000 children <5 years in Argentina) [19].

Transmission — Although found in other animals, healthy cattle are the main vectors of STEC, with the bacteria present in the cattle's intestine and feces. Infection in humans occurs following ingestion of contaminated undercooked meat, unpasteurized milk or milk products, water, fruits, or vegetables [33]. A case-control prospective study found that consumption of undercooked ground beef or contact with a person with diarrhea were the major risk factors for sporadic cases of HUS [33].

Secondary human-to-human contamination is also possible [16,33]. Transmission between children in daycare centers is a concern, and outbreaks (STEC O111 and O26) in kindergarten classrooms have been reported [23]. STEC-HUS also occurs in siblings due to the same contamination or due to human-to-human transmission [33]. In addition, there is one case report of neonatal HUS due to maternal transmission from a healthy mother who was an asymptomatic carrier of STEC [34].

A more detailed discussion on the epidemiology of STEC is found separately. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Epidemiology'.)

TYPICAL COURSE — Children with STEC-HUS typically have a prodromal illness with abdominal pain, vomiting, and diarrhea that generally precedes the development of HUS by 5 to 10 days (figure 1) [15,16,35,36]. The diarrhea starts out nonbloody and progresses to bloody diarrhea in 60 to 90 percent of cases [8,37]. Associated gastrointestinal complaints may mimic those of ulcerative colitis, other enteric infections, and appendicitis. (See "Management of mild to moderate ulcerative colitis in children and adolescents" and "Acute appendicitis in children: Clinical manifestations and diagnosis" and "Lower gastrointestinal bleeding in children: Causes and diagnostic approach".)

DIAGNOSTIC TRIAD — HUS is defined by a prodrome of diarrhea followed by the sudden onset of the following triad (figure 1):

●Microangiopathic hemolytic anemia with fragmented erythrocytes (ie, schistocytes)

●Thrombocytopenia

●Kidney involvement, indicated by elevated serum creatinine and/or hematuria and proteinuria

Microangiopathic hemolytic anemia — Microangiopathic hemolytic anemia in HUS is caused by nonimmune red blood cell (RBC) destruction due to shearing of the RBCs through platelet microthrombi. It is characterized by the following:

●Hemoglobin levels usually less than 8 g/dL.

●Negative direct antiglobulin test (formerly referred to as Coombs test).

●Peripheral blood smear with a large number (up to 10 percent of red cells) of schistocytes caused by RBC fragmentation. Typical shapes of schistocytes include helmet cells and microspherocytes (picture 1A-B).

Additional findings of hemolysis include:

●Increased serum indirect bilirubin concentration

●Reduced serum haptoglobin concentration

●Elevated serum lactate dehydrogenase

Although hemolysis may recur over a several-week period, there is no correlation between the severity of anemia and the severity of renal disease. (See "Overview of hemolytic anemias in children" and "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Microangiopathic hemolytic anemia (MAHA)'.)

Thrombocytopenia — Thrombocytopenia is characterized by a platelet count below 140,000/microL, usually approximately 40,000/microL. Despite this, there is usually no purpura or active bleeding. The degree of thrombocytopenia is unrelated to the severity of renal dysfunction. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)

Kidney involvement — The severity of kidney involvement ranges from hematuria and proteinuria to severe acute kidney injury (AKI) and oligoanuria. AKI in patients with STEC-HUS is defined as a reduction in glomerular filtration rate, which typically presents as an elevated serum creatinine. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Definition'.)

Hemoglobinuria/hematuria is a constant finding in patients with STEC-HUS. In one retrospective study, hematuria was present in all children with HUS [14]. All these patients had bloody diarrhea associated with E. coli carrying Shiga toxin 2 (Stx2) alone or in combination with Shiga toxin 1 (Stx1).

Other clinical findings of kidney involvement may include:

●Severe AKI – Severe AKI occurs in one-half of cases. As many as one-half to two-thirds of patients with HUS require dialysis during the acute phase [11]. Dehydration at the time of admission appears to be associated with a need for dialysis therapy [38]. The prognosis for recovery of renal function is generally favorable, even in patients in whom dialysis therapy was performed. (See "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Prevention' and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Prognosis'.)

AKI in children is discussed in detail separately. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis".)

●Hypertension – Hypertension is common, particularly after the administration of excess fluids or blood transfusions.

Kidney pathology — Renal biopsy is rarely needed, as the diagnosis is made on the basis of clinical findings. Renal biopsy is indicated when the diagnosis is uncertain and the degree of thrombocytopenia is not limiting.

Pathologically, STEC-HUS is associated with thrombotic microangiopathy (TMA) of the renal glomeruli, which can extend to the afferent arterioles. Three types of involvement of the renal parenchyma are observed [39,40]:

●A glomerular TMA characterized by a thickening of the capillary walls, with a double-contour appearance due to a widening of the subendothelial space (picture 2). Endothelial cells are swollen and may obstruct the capillary lumen. The lesions affect the preglomerular arterioles and the glomerular capillaries, and the mesangial matrix has a fibrillar appearance. The glomeruli are enlarged and the capillaries may contain red cells and platelets. Lesions of glomerular thrombotic microangiopathy affect a variable proportion of the glomeruli.

●Cortical necrosis may be patchy or, more rarely, diffuse and affect the entire superficial cortex. These lesions are observed in the more severe cases of STEC-HUS with prolonged anuria, and they carry a high risk of chronic renal failure.

●Although more often observed in cases of non-STEC-HUS, a pattern of predominant arterial TMA can be observed with STEC-HUS. In this pattern of arterial TMA, which is unusual in children with STEC-HUS, arterioles and interlobular arteries are severely affected with intimal edema, necrosis of the arteriolar wall, luminal narrowing, and thrombosis (picture 3A-D). Glomeruli appear ischemic and shrunken, with splitting of the capillary wall and wrinkling of the glomerular basement membrane. This lesion is responsible for severe hypertension [41].

OTHER ORGAN INVOLVEMENT — HUS commonly affects other organ systems, causing microvascular injury with swollen endothelial cells and microthrombi. Other systems involved may include [42,43]:

●Central nervous system (CNS) – Manifestations of CNS involvement include altered mental status, seizures, coma, stroke, hemiparesis, and cortical blindness [44]. Major CNS abnormalities are typically seen in up to 20 to 33 percent of cases [11,44,45]. In patients with severe neurologic findings, brain magnetic resonance imaging reveals bilateral hypersignal on T2-weighted and hyposignal on T1-weighted images in the basal ganglia, thalami, and brainstem [46]. Severe CNS involvement is associated with increased mortality.

In addition, severe hypertension may result in CNS symptoms and require emergent therapy to decrease blood pressure. The presence of severe hypertension and the response to antihypertensive therapy differentiate CNS involvement due to elevated blood pressure from primary CNS involvement. (See "Approach to hypertensive emergencies and urgencies in children", section on 'History'.)

●Gastrointestinal tract – Any area from the esophagus to the perianal area can be involved. The more serious manifestations include severe hemorrhagic colitis (which may be misdiagnosed as ulcerative colitis), bowel necrosis and perforation, rectal prolapse, peritonitis, and intussusception [47,48]. Transmural necrosis of the colon may lead to subsequent colonic stricture [49].

Hepatomegaly and/or increased serum transaminases are frequent findings.

●Cardiac – Cardiac dysfunction may be due to fluid overload, hypertension, or hyperkalemia. Direct cardiac involvement has also been reported, including thrombotic microangiopathy, myocarditis, and pericardial disease including cardiac tamponade [50-54]. Cardiac ischemia is detected by elevated levels of troponin 1 [55,56].

●Endocrine – During the acute phase, up to 10 percent of patients develop glucose intolerance. Transient diabetes mellitus may occur, and rarely permanent diabetes mellitus, which may develop years later [47,57,58].

EVALUATION — An expedited and accurate assessment for HUS is required for a patient with a recent history of diarrhea (possibly bloody) who presents with symptoms and signs of a multisystem disorder (algorithm 1).

In whom to suspect hemolytic uremic syndrome — HUS should be suspected in a child with a recent history of diarrhea (possibly bloody) and signs of systemic illness (algorithm 1), including:

●Decreased urine volume in an adequately hydrated child (indicating kidney injury)

●Recent onset of paleness (indicating anemia) or bruising (indicating thrombocytopenia)

Patients without diarrhea — In a small minority of patients, the characteristic prodrome of diarrhea is absent. In this case, the presence of the diagnostic triad in an age-appropriate child should still lead to the likely diagnosis of STEC-HUS. The lack of diarrhea should prompt consideration of infection of other organs, particularly the urinary tract, with a Shiga toxin-producing organism [59]. The diagnosis of STEC-HUS is confirmed by polymerase chain reaction (PCR) testing on rectal swab and/or urine.

Laboratory evaluation — The initial laboratory evaluation (algorithm 1) should include:

●Complete blood count to detect any evidence of anemia or thrombocytopenia. In addition to anemia and thrombocytopenia, leukocytosis is common in diarrhea-induced HUS.

●Kidney function studies including blood urea nitrogen and serum creatinine.

●Urinalysis to detect hematuria and/or hemoglobinuria.

In patients with the diagnostic triad of anemia, thrombocytopenia, and kidney involvement (ie, elevated serum creatinine, and/or hematuria and proteinuria), the peripheral smear should be reviewed for evidence of a microangiopathic pattern with a large number of schistocytes and helmet cells (picture 1A and picture 1B). (See 'Microangiopathic hemolytic anemia' above and 'Typical course' above.)

Testing for STEC infection — Patients in whom HUS is suspected should have an evaluation for STEC infection. In our center, testing includes:

●PCR testing for Shiga toxins from a rectal swab or stool specimen. PCR testing can detect the presence of Stx1 and/or Stx2 genes.

●Stool culture using media to promote the growth of the O157:H7 strain of E. coli. This is typically done with sorbitol MacConkey agar enriched with tellurite. Selective media are required to identify non-O157:H7 STEC. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Microbiology' and "Shiga toxin-producing Escherichia coli: Clinical manifestations, diagnosis, and treatment", section on 'Microbiologic diagnosis'.)

Stool samples should be obtained rapidly, because STEC infection is caused by a low load of organisms, and excretion in the stools lasts only a few days after the onset of diarrhea [60]. If stool cannot be obtained, rectal swabs should be performed [37]. A negative stool culture does not rule out the diagnosis of STEC infection because the bacteria may not be detected by culture from stool samples even if they are present.

●Although failure to detect STEC in the stool of a patient with STEC-HUS is rare, this should not rule out the diagnosis of STEC-HUS. Serum antibodies to lipopolysaccharide of STEC, if available, may aid in the diagnosis of STEC when the stool screen for STEC is negative. These antibodies persist in the serum for several weeks [61].

DIAGNOSIS — The diagnosis of STEC-HUS in children is made on clinical grounds based on the characteristic clinical and laboratory findings previously described: a prodrome of diarrhea due to a Shiga toxin-producing bacteria, followed by abrupt onset of the diagnostic triad (see 'Typical course' above and 'Diagnostic triad' above and 'Evaluation' above):

●Microangiopathic hemolytic anemia

●Thrombocytopenia

●Kidney involvement, indicated by elevated serum creatinine and/or hematuria and proteinuria [62]

Diagnosis of STEC-HUS is confirmed by a positive test for Shiga toxin (ie, polymerase chain reaction [PCR] on stool or rectal swab, stool culture). Of note, diarrhea may be absent in a small number of patients with STEC-HUS. The absence of diarrhea should not rule out the diagnosis of STEC-HUS [59]. (See 'Evaluation' above.)

In most patients, treatment is initiated based on the clinical diagnosis of HUS. Renal biopsy, which is rarely needed, may be helpful in selected patients in whom the diagnosis is uncertain and the procedure is not contraindicated by severe thrombocytopenia. (See 'Kidney pathology' above and "Overview of hemolytic uremic syndrome in children".)

DIFFERENTIAL DIAGNOSIS — The constellation of clinical and laboratory findings typical of STEC-HUS in children is similar to that found in other disorders. These include:

●Other enteric infections – The combination of severe diarrhea and renal insufficiency seen in other enteric infections (such as Salmonella, Campylobacter, Yersinia, amebiasis, and Clostridioides difficile) may be confused with that caused by HUS. The severe abdominal pain, frankly bloody diarrhea, fever, and leukocytosis seen with these infections are similar to the prodrome seen in STEC-HUS. In addition, patients with severe diarrhea can have elevations in serum creatinine and blood urea nitrogen, but this is typically due to volume depletion, not intrinsic renal disease. This constellation of findings in the absence of thrombocytopenia and hemolytic anemia distinguishes these enteric infections from HUS.

●Non-STEC HUS – It can be challenging to differentiate STEC-HUS from other causes of HUS because the clinical presentations can be similar. Although non-STEC-HUS does not usually present with a diarrheal prodrome, approximately one-quarter of patients with complement-mediated HUS (the second most common cause of HUS) will have an antecedent trigger of a diarrheal illness. Moreover, some cases of STEC-HUS may not present with colitis and diarrhea. Furthermore, the alternative complement pathway may be transiently activated during the acute phase of STEC-HUS [63,64], and STEC can trigger HUS episodes in patients with complement mutation, mostly in those with membrane cofactor protein (MCP) mutation [65]. Nevertheless, clinical and laboratory manifestations typically differentiate STEC-HUS from the two most common causes of non-STEC-HUS, as follows:

•Pneumococcal-associated HUS – Affected patients have concurrent serious pneumococcal infection (eg, pneumonia or meningitis) and no evidence of Shiga toxin on stool polymerase chain reaction (PCR) and/or culture. (See "Overview of hemolytic uremic syndrome in children", section on 'Streptococcus pneumoniae'.)

•Complement-mediated HUS – These patients generally have a severe clinical course, recurrent disease, and often a positive family history. Genetic testing or identifying antibodies to complement components confirms the diagnosis of complement-mediated HUS. These patients also have no evidence of Shiga toxin on stool PCR and/or culture. (See "Complement-mediated hemolytic uremic syndrome in children".)

Shigella dysenteriae type 1-associated HUS occurs in India, Bangladesh, and southern Africa. Although the pathogenesis of disease is similar to that of HUS induced by O157 E. coli infection, the disease is usually more severe, with an acute mortality rate of 15 percent and over 40 percent of patients developing chronic kidney disease [32]. Shigella HUS is discussed separately. (See "Shigella infection: Epidemiology, clinical manifestations, and diagnosis" and "Shigella infection: Treatment and prevention in children".)

●Thrombotic thrombocytopenic purpura (TTP) – TTP is rare in children and is characterized by the association of thrombocytopenia, microangiopathic hemolytic anemia, renal involvement, and neurologic symptoms. TTP is secondary to a deficiency of the ADAMS-13 protease which normally cleaves the von Willebrand factor multimers. In children, the ADAMS-13 deficiency is a rare autosomal recessive disorder. In adults, the disease is most often secondary to autoantibodies against ADAMTS13.

●Disseminated intravascular coagulation (DIC) – As in STEC-HUS, patients with DIC also have thrombocytopenia, hemolytic anemia, and kidney injury. However, patients with DIC have abnormal coagulation studies (prolongation of the prothrombin time [PT] and activated partial thromboplastin time [aPTT]), and patients with HUS have normal coagulation studies. The distinction between HUS and DIC can be challenging; it is based upon the history and laboratory studies [66]. Contrary to DIC, HUS patients rarely have active bleeding. DIC is associated with intravascular activation of the coagulation cascade, leading to intravascular deposition of fibrin thrombi, the consumption of all the components of this cascade, and microangiopathic hemolytic anemia. As a result, patients with DIC typically have thrombocytopenia, as do patients with STEC-HUS. However, patients with DIC also have elevated D-dimer, normal haptoglobin levels, low circulating levels of fibrinogen and factors V and VIII, and elevation of the PT and aPTT, which is not generally seen in patients with HUS [66]. (See "Disseminated intravascular coagulation in infants and children" and "Overview of hemolytic uremic syndrome in children", section on 'Differential diagnosis'.)

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

●Microbiology – Most cases of hemolytic uremic syndrome (HUS) are due to an infection with Shiga toxin-producing Escherichia coli (STEC), which accounts for 90 percent of pediatric cases of HUS. (See 'Microbiology' above and 'Epidemiology' above and 'Kidney pathology' above.)

●Typical course – Children with STEC-HUS typically have a prodromal illness with abdominal pain, vomiting, and diarrhea (sometimes bloody) that precedes the development of HUS by approximately 5 to 10 days (figure 1). (See 'Typical course' above.)

Diarrhea may be bloody or nonbloody. In a small minority of cases, diarrhea may be absent.

●Diagnostic triad – HUS presents suddenly with the following classical findings (see 'Diagnostic triad' above):

•Microangiopathic hemolytic anemia – Hemoglobin levels are usually less than 8 g/dL. Direct antiglobulin test is negative, and the peripheral blood smear is characterized by the large number of schistocytes and helmet cells (picture 1A-B). There is no correlation between the severity of the anemia and the severity of the kidney disease. (See 'Microangiopathic hemolytic anemia' above.)

•Thrombocytopenia – Platelet counts are generally around 40,000/microL. There is no correlation between the degree of thrombocytopenia and the severity of the kidney disease. (See 'Thrombocytopenia' above.)

•Kidney involvement – The severity of kidney involvement ranges from hematuria and proteinuria to acute kidney injury (AKI; ie, elevated serum creatinine), to severe kidney failure and oligoanuria, which occur in one-half of cases. Hypertension is also frequently observed. Although as many as 50 percent of those with HUS require dialysis during the acute phase, the prognosis for recovery of kidney function is generally favorable. (See 'Kidney involvement' above.)

●Other organ involvement – Other organ systems that may be involved include the central nervous system (CNS), gastrointestinal tract, heart, pancreas, and liver. Severe CNS involvement (eg, seizures, coma, and stroke) is associated with significant mortality. (See 'Other organ involvement' above.)

●Evaluation – An expedited and accurate assessment for HUS (algorithm 1) is required for a patient with a recent history of diarrhea (possibly bloody) who presents with symptoms and signs of a multisystem disorder. The initial evaluation comprises a complete blood count to detect any evidence of anemia or thrombocytopenia and renal function studies, including serum creatinine. In those patients with anemia, thrombocytopenia, and elevated serum creatinine, further investigation includes reviewing the peripheral smear for evidence of a microangiopathic pattern with a large number of schistocytes and helmet cells (picture 1A-B) and screening for a STEC infection. (See 'Evaluation' above.)

●Diagnosis – The diagnosis of STEC-HUS in children is generally made on clinical grounds from the characteristic clinical course and laboratory findings. The typical course includes a diarrheal prodrome followed by the sudden onset of the diagnostic triad (see 'Diagnosis' above):

•Microangiopathic hemolytic anemia

•Thrombocytopenia

•Kidney involvement, indicated by elevated serum creatinine and/or hematuria and proteinuria

Shiga toxin exposure is confirmed by a positive test for Shiga toxin from either a stool or rectal swab using polymerase chain reaction (PCR), or a positive stool culture.

●Differential diagnosis – The differential for STEC-HUS includes other enteric infections, non-STEC HUS, thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC). (See 'Differential diagnosis' above.)