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 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 (HUS) 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 — Traditionally, HUS had been divided into diarrhea-positive and diarrhea-negative HUS. The former, 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.
The following classification is based on a better understanding of the various causes of HUS (see "Overview of hemolytic uremic syndrome in children"):
●Primary causes without coexisting disease (also referred to as atypical HUS) [2,3]:
•Complement gene mutations
•Antibodies to complement factor H
•Diacylglycerol kinase epsilon gene mutations
•Inborn error of cobalamin C metabolism
●Secondary causes:
•Infection:
-STEC
-Streptococcus pneumoniae
-Human immunodeficiency viral infection
•Drug toxicity, particularly in patients with cancer or solid organ transplant recipients
•Rare occurrences in pregnant patients or in those with autoimmune disorders (eg, systemic lupus erythematosus)
In addition, 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. For this topic, patients identified as either having typical or diarrhea-positive HUS would be diagnosed with secondary HUS due to STEC. In addition, verotoxin, an alternate term for Shiga toxin, also has been used extensively in the literature.
MICROBIOLOGY — STEC-HUS occurs after an infection with Shiga toxin-producing enterohemorrhagic E. coli (STEC) and accounts for almost all the cases of postdiarrheal HUS in the United States [4-7]. 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 [8].
E. 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. Shiga toxin-producing Escherichia coli (STEC) fall into two clinically relevant categories: those that contain a gene encoding Shiga toxin 2 (with or without a gene encoding Shiga toxin 1) and those that do not (ie, their only Shiga toxin gene encodes Shiga toxin 1 [Stx1]) (table 1). Shiga toxin 2 (Stx2) production is associated with hemolytic uremic syndrome (HUS) [9-11]. In a prospective multicenter study of 4767 children with blood diarrhea, 34 of 214 with identified STEC infection developed HUS [10,12]. 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 [13,14]. (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 as illustrated by the following:
●In the United States and in Europe, STEC-HUS E. coli 0157:H7 has been the most frequent strain associated with HUS in children [9,15,16]. Almost all E. coli O157:H7 contain a gene encoding Shiga toxin 2. However, other strains have become more common including O26, O111, O121, O145, O91, O103, O104, and O80 [3,17-20].
•In May 2011, a previously unknown strain, E. coli O104:H4, was identified as the cause of STEC-HUS in a large outbreak in Germany [20-23]
•In Italy, the primary strain has been E. coli 026 [24].
•The French pediatric HUS surveillance system has found a decline in STEC O157-related pediatric HUS and the emergence of STEC O26 and STEC O80 in France over the period 2007 to 2016 [25].
●In Latin America, E. coli 0157:H7 remains the predominant strain (>70 percent) [3].
●In Australia, approximately one-half of cases of postdiarrheal HUS are due to E. coli 0111 [26,27]. There has also been an outbreak of E. coli 0111 infections in the United States, in which 26 of 156 patients developed HUS [28].
Shigella — 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 [29]. (See "Shigella infection: Clinical manifestations and diagnosis", section on 'Hemolytic-uremic syndrome'.)
EPIDEMIOLOGY — STEC-HUS accounts for over 90 percent of cases of HUS in children. It principally affects children under the age of five years [3]. 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 three to five years of age [3,9]. The incidence of STEC-HUS in Latin America remains ten times higher than in other continents (10 to 17 cases per 100 000 children <5 years in Argentina) [17].
A study from a voluntary surveillance system of 31 French pediatric nephrology units reported an incidence of 0.7 cases per 100,000 children less than 15 years and a higher incidence of two per 100,000 children less than five years of age [30]. A case-control prospective study from the same French surveillance system showed that consumption of undercooked ground beef or contact with a person with diarrhea were the major risk factors for sporadic cases of HUS [31]. Outbreaks (STEC O111 and O26) due to person-to-person transmission occurred in two different kindergartens [25].
Although found in other animals, healthy cattle are the main vectors of Shiga toxin-producing enterohemorrhagic E. coli, with the bacteria being present in the cattle intestine and feces. Infection in humans occurs following ingestion of contaminated undercooked meat, unpasteurized milk or milk products, water, fruits, or vegetables [31]. Secondary human to human contamination is also possible [14,31]. Thus, transmission from child to child in day-care centers is a concern. STEC-HUS also occurs in siblings a few days or weeks apart due to the same contamination or due to human to human transmission [31]. In addition, there is a case report of neonatal HUS due to maternal transmission from a healthy mother who was an asymptomatic carrier of STEC [32].
A more detailed discussion on the epidemiology of STEC E. Coli is found separately. (See "Shiga toxin-producing Escherichia coli: Microbiology, pathogenesis, epidemiology, and prevention", section on 'Epidemiology'.)
CLINICAL AND LABORATORY MANIFESTATIONS
Overview — 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). The diarrhea and 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".)
HUS complicates 6 to 9 percent of STEC infections and usually begins 5 to 10 days after the onset of diarrhea [13,14,33,34]. HUS is defined by the sudden onset of the following triad (figure 1):
●Hemolytic anemia with fragmented erythrocytes
●Thrombocytopenia
●Acute kidney injury
The following sections provide an overview concerning the clinical and laboratory manifestations of STEC-HUS as reported in multiple studies from different geographic locations over several decades.
Microangiopathic hemolytic anemia — In HUS, the microangiopathic hemolytic anemia is caused by nonimmune red blood cell (RBC) destruction due to shearing of the RBCs through platelet microthrombi, and is characterized by the following:
●Hemoglobin levels usually less than 8 g/dL
●Negative Coombs' tests
●Peripheral blood smear with a large number of schistocytes (up to 10 percent of red cells) and helmet cells caused by the RBC fragmentation (picture 1 and picture 2)
Additional findings of hemolysis include elevation of the serum indirect bilirubin concentration and reduction in the serum haptoglobin concentration. The serum lactate dehydrogenase (LDH) level is elevated. 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/mm3 and usually approximately 40,000/mm3. 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".)
Renal manifestations — The severity of renal involvement ranges from hematuria and proteinuria to severe AKI (defined as a reduction in glomerular filtration rate typically presenting as an abnormally elevated serum creatinine) and oligoanuria (see "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Definition').
●Hemoglobinuria/hematuria is a constant finding. In one retrospective study, hematuria was present in all children with HUS [12]. All these patients had bloody diarrhea associated with Escherichia coli carrying Stx2 alone or in combination with Stx1.
●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 [9]. Dehydration at the time of admission appears to be associated with a need for dialysis therapy [35]. 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 (HUS) in children", section on 'Prevention' and "Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) 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 is common, particularly after the administration of excess fluids or blood transfusions.
Other organ involvement — HUS commonly affects other organ systems, including [36,37]:
●Central nervous system – Manifestations of central nervous system (CNS) involvement include altered mental status, seizures, coma, stroke, hemiparesis, and cortical blindness [38]. Major CNS abnormalities are typically seen in up to 20 to 33 percent of cases [9,38,39]. 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 [40]. 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 differentiates CNS involvement due to elevated blood pressure. (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 [41,42].Transmural necrosis of the colon may lead to subsequent colonic stricture [43].
●Cardiac dysfunction – 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 [44-48]. Cardiac ischemia is detected by elevated levels of troponin 1 [49,50].
●Pancreas – 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 [41,51,52].
●Liver – Hepatomegaly and/or increased serum transaminases are frequent findings.
●Hematology – In addition to anemia and thrombocytopenia, leukocytosis is common in diarrhea-induced HUS; the prognosis is worse with increased white blood cell counts [53].
PATHOLOGY — Pathologically, STEC-HUS is associated with glomerular thrombotic microangiopathy (TMA), which can extend to the afferent arteriole. Three types of involvement of the renal parenchyma are observed [54,55]:
●A glomerular thrombotic microangiopathy, characterized by a thickening of the capillary walls, with a double-contour appearance due to a widening of the subendothelial space (picture 3). 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 thrombotic microangiopathy 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 4 and picture 5 and picture 6 and picture 7). 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 [56].
The need for renal biopsy is rare, as the diagnosis is made on the basis of the clinical findings. Renal biopsy is indicated when the diagnosis is uncertain and the degree of thrombocytopenia is not limiting.
Microvascular injury with swollen endothelial cells and microthrombi are also seen in other organs including the colon, central nervous system, pancreas, and myocardium.
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. As examples, in a child who had a recent diarrheal illness, findings of decreased urine volume in an adequately hydrated child (renal injury), or recent onset of paleness (anemia), bruising (thrombocytopenia), or lethargy should prompt the consideration of HUS.
In these patients, the diagnostic work-up should include 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 1 and picture 2), and screening for a STEC infection. (See 'Clinical and laboratory manifestations' above.)
Evidence of STEC infection — In our center, an evaluation is performed to detect STEC infection that includes testing for Shiga toxins (polymerase chain reaction [PCR] stool testing for the presence of ST-1 and/or ST-2 genes) in the stool and stool cultures. Stool culture should be performed using sorbitol MacConkey agar, enriched with tellurite to promote the growth of the O157:H7 strain of E. coli. 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'.)
However, results from stool cultures may be unreliable because the bacteria are only present in the stools for a few days and, even if present, may not be detected by culture from stool samples.
Serum antibodies to lipopolysaccharide of STEC persist for several weeks and may be of added value in the diagnosis of STEC [57].
DIAGNOSIS — The diagnosis of STEC-HUS in children is generally 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 characteristic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (eg, abnormally elevated serum creatinine) [58] . (See 'Clinical and laboratory manifestations' above.)
However, in a small minority of patients, the characteristic prodrome of diarrhea is absent. In this setting, the presence of the defining triad in an age appropriate child should prompt consideration of infection of other organs, particularly the urinary tract, with a Shiga toxin-producing organism. The diagnosis is confirmed with serologic testing, a positive microbial culture for STEC, or detection of virulence genes or free Shiga toxin in fecal samples [58]. (See 'Evidence of STEC infection' above.)
In most patients, treatment is initiated based on the clinical diagnosis of HUS of the triad of microangiopathic hemolytic anemia with fragmented red blood cells, thrombocytopenia, and acute kidney injury. Renal biopsy, which is rarely performed, may be helpful in selected patients in whom the diagnosis is uncertain and thrombocytopenia is not limiting. In general, patients with STEC-associated HUS will have renal parenchymal findings of glomerular thrombotic microangiopathy. In contrast, other causes of HUS (eg, complement-mediated HUS) will typically have a predominant arterial thrombotic microangiopathy pattern. (See 'Pathology' above.)
DIFFERENTIAL DIAGNOSIS — The constellation of clinical and laboratory findings of typical HUS in children can be mimicked by several disorders, such as the following:
●Severe abdominal pain, frankly bloody diarrhea, fever, and leukocytosis occur in other enteric infections (such as Salmonella, Campylobacter, Yersinia, amebiasis, and Clostridioides difficile. With severe diarrhea, elevations in the serum creatinine concentration and blood urea nitrogen (BUN) are typically due to volume depletion, not intrinsic renal disease. Thus, the combination of severe diarrhea and renal insufficiency due to volume depletion may be confused with that due to HUS. This constellation of findings in the absence of thrombocytopenia and hemolytic anemia distinguishes these enteric infections from HUS.
●The combination of thrombocytopenia, hemolytic anemia, and renal injury can also occur in disseminated intravascular coagulation (DIC) and other forms of HUS.
•The distinction between HUS and DIC is more difficult, and is based upon the history and laboratory studies [59]. DIC is associated with intravascular activation of the coagulation cascade, leading to intravascular deposition of fibrin thrombi, the consumption of all of the components of this cascade, and microangiopathic hemolytic anemia. As a result, patients with DIC typically have thrombocytopenia, elevated D-dimer, normal haptoglobin levels, low circulating levels of fibrinogen and factors V and VIII, and prolongation of the prothrombin and partial thromboplastin times (PT and aPTT, respectively), which is not generally seen in patients with HUS [59]. These patients are differentiated from those with HUS due to the abnormal coagulation studies. (See "Disseminated intravascular coagulation in infants and children" and "Overview of hemolytic uremic syndrome in children", section on 'Differential diagnosis'.)
•Non-STEC-HUS – It can be challenging differentiating STEC-HUS from other causes of HUS. 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 antecedent trigger of a diarrheal illness, and as previously mentioned, 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 [60,61] and STEC can trigger HUS episodes in patients with complement mutation, mostly in those with membrane cofactor protein (MCP) mutation [62]. Nevertheless, clinical and laboratory manifestations typically differentiate STEC-HUS from the two most common causes of non-STEC-HUS:
-Pneumococcal-associated HUS – Affected patients have concurrent serious pneumococcal infection (eg, pneumonia or meningitis). (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. (See "Complement-mediated hemolytic uremic syndrome in children".)
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
●Introduction and epidemiology – The hemolytic uremic syndrome (HUS) is characterized by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Most cases of HUS are due to an infection with Shiga toxin-producing Escherichia coli (STEC), which accounts for 90 percent of pediatric cases of HUS. (See 'Introduction' above and 'Epidemiology' above and 'Classification' above.)
●Clinical manifestations – Children with STEC-HUS typically have a prodromal illness with abdominal pain, vomiting, and diarrhea (usually bloody) that immediately precedes the development of HUS (figure 1). Five to 10 days after the onset of diarrhea, HUS presents suddenly with the following classical findings (see 'Clinical and laboratory manifestations' above):
•Microangiopathic hemolytic anemia – Hemoglobin levels are usually less than 8 g/dL. The Coombs' test is negative and the peripheral blood smear is characterized by the large number of schistocytes and helmet cells (picture 1 and picture 2). There is no correlation between the severity of the anemia and the severity of the renal disease.
•Thrombocytopenia – Platelet counts are generally around 40,000/mm3. There is no correlation between the degree of thrombocytopenia and the severity of the kidney disease.
•Acute kidney injury – The severity of kidney involvement ranges from hematuria and proteinuria 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.
•Other organ systems including 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 'Clinical and laboratory manifestations' above.)
●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. 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 1 and picture 2), 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 and laboratory findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury following a diarrheal prodrome due to STEC. The demonstration of Shiga toxin exposure relies on one of the following: positive stool culture or detection of Shiga toxin genes in stools by polymerase chain reaction (PCR). (See 'Diagnosis' above.)
●Differential diagnosis – The differential for STEC-HUS includes other enteric infections, disseminated intravascular coagulation, and non-STEC-HUS. (See 'Differential diagnosis' above.)
