An Overview of Pediatric Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS) is one of the main causes of community-acquired acute kidney injury (AKI). AKI is responsible for significant morbidity and mortality in the pediatric population. Pediatricians must understand the new nomenclature of HUS as well as recognize the different signs and symptoms of this entity to initiate prompt treatment.After completing this article, readers should be able toIdentify the signs and symptoms of HUS.Discuss the initial evaluation and management of suspected HUS.Describe the updated terminology for classifying HUS.Make pertinent subspecialty referrals to support patients with HUS.Discuss the prognosis of HUS.A previously healthy 4-year-old girl with incomplete vaccinations presented for an evaluation of 5 days of fever (T-max 39 °C), severe cough, increased work breathing, and chest and back pain. Laboratory analysis revealed a white blood cell count of 10.4 10K/μL, anemia with a hemoglobin of 9.2 g/dL, thrombocytopenia with a platelet count of 12 610 K/μL, C-reactive protein of 38.9 mg/dL, and procalcitonin of 440 ng/mL. Coagulation studies were abnormal, with a prothrombin time (PT) of 19.3 seconds (nl 11.6–15.4 seconds), partial thromboplastin time (PTT) of 65.3 seconds (nl 22.8–38.2 seconds), and fibrinogen of 1055 mg/dL. Renal function was normal. A chest radiograph demonstrated a near-complete whiteout of the right hemithorax with a pleural effusion. Such findings were confirmed by an ultrasound and computed tomography scan, which showed necrotizing pneumonia with a significantly large complex pleural effusion. A blood culture was obtained, and the patient was started on broad-spectrum antibiotics for pneumonia. Soon after admission, the patient decompensated with worsening respiratory distress, decreased urine output with a 3-L positive fluid balance, and hypertension. Repeat laboratory studies showed worsening anemia with a hemoglobin of 8.7 g/dL and worsening thrombocytopenia with a platelet count of 2110 K/μL. Additional tests to check for hemolysis demonstrated a lactate dehydrogenase (LDH) of 5589 IU/L, uric acid of 6.3 mg/dL, haptoglobin of <20 mg/dL, a Coombs-positive result, and the presence of schistocytes identified on a blood smear. The patient also developed intrarenal acute kidney injury (AKI) with a creatinine of 1.37 mg/dL and blood urea nitrogen of 62 mg/dL and required hemodialysis. The patient was in multiorgan failure; she was intubated and started on mechanical respiratory support. A chest tube was placed, and pleural fluid cultures were positive for Streptococcus pneumoniae. Stool culture was negative for Shiga toxin–producing Escherichia coli (STEC). Further studies showed low complement levels: C3 level of 49.2 mg/dL (92–184 mg/dL), C4 level of 4.5 mg/dL (20–59 mg/dL), elevated soluble terminal complement complex enzyme (SC5b-9) of 1415 ng/mL (normal <244 ng/mL), and normal “a thrombospondin type 1 motif, member 13” (ADAMTS13) activity of 38%. These findings were consistent with HUS secondary to S. pneumoniae. The patient received 4 doses of eculizumab with a good response; she completed antibiotic treatment, did not develop significant sequelae, and was later discharged.Thrombotic microangiopathies (TMAs) are a group of disorders characterized by injury and occlusion of microvessels that arise from an endothelial injury, resulting in tissue ischemia and end-organ damage. The TMA umbrella includes but is not limited to HUS, thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulopathy (DIC). Given the overlap between presentations, TMAs represent a diagnostic and therapeutic challenge for clinicians.1 Due to the critical nature of acute TMAs, a significant proportion of affected patients require admission to the intensive care unit upon presentation, many of whom are not diagnosed at the time of admission. A thorough clinical and laboratory evaluation is essential to arrive at an accurate diagnosis, which is key for appropriate management. HUS is a TMA that mainly affects the kidneys and is the most common cause of TMA in young children.2 HUS is classically defined by the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and AKI. HUS can be primary or secondary, both of which vary widely in severity and treatment. This article outlines the current nomenclature for HUS as well as the initial diagnostic evaluation and management of HUS, particularly of primary HUS, STEC-HUS, and S. pneumoniae HUS.Historically, HUS was classified as “diarrhea positive” (typical) and “diarrhea negative” (atypical). STEC-HUS was referred to as typical HUS. All other causes of HUS were referred to as atypical HUS. Often, children with atypical HUS had persistent or recurrent disease, and some had a family history of HUS. These observations contributed to significant advances in the understanding of the etiology and pathophysiology of HUS, particularly the role of the alternative complement pathway. The terminology for HUS is constantly evolving as our understanding of its pathophysiology improves (Figure 1). HUS should be referred to as primary or secondary HUS based on the pathophysiology. Primary HUS, formerly referred to as atypical, is a disorder of complement regulation due to an underlying genetic predisposition. Secondary HUS, formerly referred to as typical, is caused by an internal or external event (infection, malignancy, transplantation, drugs, autoimmune disease).TTP is a primary TMA syndrome caused by a severe reduction in the function of the von Willebrand factor–cleaving protease ADAMTS13, which promotes the formation of platelet microthrombi. TTP is classically described by the following pentad: MAHA, thrombocytopenia, fever, neurologic symptoms, and AKI. Among the primary TMA syndromes, TTP is remarkable for causing minimal kidney function abnormalities.DIC is an acquired systemic syndrome of the coagulation system resulting in consumptive coagulopathy, leading to hemorrhage and pathologic thrombosis.Most pediatric HUS cases worldwide are due to a STEC infection (Figure 2). A total 90% of HUS cases are related to Shiga toxin–producing bacteria (E. coli, Shigella dysenteriae), 5% of cases are attributed to S. pneumoniae or other secondary causes, and primary HUS accounts for 5% of cases. STEC-HUS is a disease of children mainly aged younger than 5 years; the incidence peaks during summer and fall and varies depending on geographic location.3 In North America and Europe, the annual incidence is 1.9 to 2.9 cases per 100 000 children aged 3 to 5 years. However, the incidence of STEC-HUS in Latin America is 10 times higher.4 Of the patients with sporadic STEC gastroenteritis, 5% to 10% develop HUS; however, that frequency can reach up to 20% during outbreaks.Primary HUS is a rare disorder; the annual incidence is estimated to be 0.23 to 0.42 cases per million.5The hallmark of HUS is a procoagulant and proinflammatory state of activated endothelial cells and an overactivation of the complement cascade.Complement is part of the innate immune response, assisting host cells in eliminating pathogens through 3 distinct pathways: classical, lectin, and alternative. These pathways converge to produce C3 convertase, a complex that initiates the formation of the C5-9 membrane attack complex (MAC) to destroy target cells by adhesion and lysis.6 Activation of the MAC causes endothelial cell swelling and microvascular thrombosis, particularly in the kidneys and, to a lesser extent, other organs. The endothelial damage results in hemolysis, which can lead to further complement activation, endothelial injury, platelet aggregation, and microthrombi, which in turn causes further hemolysis that can lead to further complement activation, initiating a vicious cycle.7 Hemolysis is due to intravascular red blood cell fragmentation. Complement activation can be initially triggered by any stress on the body, such as an infection, surgery, or inflammation.Primary HUS is a disorder of complement regulation due to an underlying genetic predisposition. In healthy conditions, the complement alternative pathway is constantly “on” but tightly controlled. However, in primary HUS, the complement alternative pathway is inappropriately activated through gain-of-function mutations (CFB or C3) or is uninhibited via loss-of-function mutations (CFH, CFI, MCP, THBD) of complement regulators or via autoantibodies to CFH.1 The initial activation of complement is usually triggered by stress to the body. Overactivation of complement can be sustained or relapsing, leading to poor outcomes.There are other rare genetic conditions that lead to permanent endothelial cell activation, such as coagulation disorders, DKGε mutations, metabolism defects, and cobalamin C deficiency.7Secondary HUS is caused by an internal or external event, such as infections (STEC, S. dysenteriae, S. pneumoniae, influenza virus infections), cancer, transplantation, autoimmunity, or drugs. In these scenarios, once the trigger is removed or controlled, the HUS usually abates.STEC-HUS is the most common cause of secondary HUS and the overall most common cause of HUS in the pediatric population.5 Shiga toxin–producing bacteria, particularly the high-risk Shiga toxin 2 serotype bacteria, can precipitate this HUS.8 The most common E. coli serotype is E. coli O157:H7. Other non-O157 STEC strains and other Shiga toxin–producing bacteria, such as S. dysenteriae, have also been identified.8 The most common reservoir of E. coli O157:H7 is healthy cattle, which transmit E. coli O157:H7 through their feces. Thus, infection in humans occurs after consumption of contaminated food or water (undercooked ground beef, unpasteurized dairy products, fresh produce), person-to-person contact, or contact with carrier animals. Shiga toxin is transferred into the bloodstream from the gastrointestinal tract by attaching to the cell membrane receptor Gb3. Shiga toxin is translocated into any cell that expresses the Gb3 receptor, particularly endothelial cells.8 Invasion of the toxin into endothelial cells precipitates cytotoxic damage. Microvascular injury initiates thrombotic responses such as platelet adhesion and microthrombi generation.8 Damage to endothelial cells in the kidney and large bowel can explain most of the signs and symptoms of HUS. However, other organs, including the pancreas and central nervous system, can also be involved, which can have a direct correlation with the overall extent of the disease.In the acute phase of secondary HUS, a decrease in C3 and C4 as well as an increase in complement degradation products may be observed. However, no correlation with disease severity and degree of changes in levels of C3, C4, and complement degradation products has been found.Another cause of secondary HUS in the pediatric population is that induced by S. pneumoniae. The exact pathophysiology has not been determined. The neuraminidase produced by S. pneumoniae cleaves N-acetyl neuraminic acid (sialic acid), exposing the Thomsen-Friedenreich (TF) antigen on platelets, erythrocytes, and glomerular endothelial cells. Preformed immunoglobulin M antibodies react to the expressed TF antigen, precipitating the complement cascade leading to HUS.The clinical presentation of HUS is nonspecific. Signs and symptoms include weakness, fatigue, pallor, shortness of breath, decreased urine output, and severe hypertension. Systemic signs of HUS vary significantly between patients, depending on the organs affected by the HUS process. Extrarenal manifestations include but are not limited to neurologic (eg, seizures, stroke, coma), gastrointestinal (eg, hemorrhage, perforation, pancreatitis, cholestasis), pulmonary (acute respiratory distress syndrome, respiratory failure, pleural effusion), cardiac (eg, arrhythmias, ischemia, cardiomyopathy, and pericardial effusion), and endocrine (insulin-dependent hyperglycemia).A prodromal illness with emesis, diarrhea, and abdominal pain typically precedes the development of secondary HUS precipitated by STEC. The diarrhea starts as nonbloody and progresses to bloody diarrhea in the first 3 days.8 The microangiopathic changes occur by day 8 or 9 and anuria before day 10.8 HUS almost always manifests 5 to 14 days after the onset of the prodrome. In S. dysenteriae secondary HUS, the manifestations are usually more severe. S. pneumoniae–induced HUS occurs in individuals with severe S. pneumoniae sepsis, usually presenting with complicated pneumonia and, in some cases, with meningitis.In the setting of primary HUS, the onset of the disease may follow a trigger event such as autoimmune conditions, transplantation, pregnancy, infections, drugs, or metabolic disorders. Primary HUS presentation is usually more severe and usually relapses without directed treatment.The hallmark of HUS disease is the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and AKI.Rapidly progressive thrombocytopenia is the cardinal and universal hematologic abnormality in patients with HUS. However, a transient decrease in platelet count may be observed in patients with an STEC infection who do not progress to HUS.8Thrombocytopenia is defined by a platelet count below 150 000/μL or >25% decline from baseline. The severity ranges from mild to severe. Despite the severity, there are usually no clinical signs of thrombocytopenia (no petechiae, purpura, or active bleeding).Microangiopathic hemolytic anemia is caused by nonimmune red blood cell fragmentation secondary to platelet microthrombi and is characterized by anemia and markers of hemolysis as follows: Hemoglobin levels are usually less than 8 g/dLNegative direct antiglobulin test (DAT, formerly referred to as the Coombs test; DAT can be positive in the case of pneumococcal HUS)Peripheral blood smear with schistocytes (including helmet cells and micro spherocytes; Figure 3)Increased serum indirect bilirubin concentrationReduced serum haptoglobin concentrationHemoglobinuriaElevated serum LDHAnother constant finding is severe hypertension secondary to endothelial swelling. The severity of kidney disease ranges from proteinuria and microscopic hematuria to severe AKI, gross hematuria, and oliguria requiring kidney replacement therapy.In 50% to 60% of children with secondary STEC-related HUS, oliguria is reported.8 Hemoglobinuria is a constant finding in patients with secondary STEC-related HUS, as it reflects intravascular hemolysis that exceeds the resorptive capacity of the kidneys.The diagnostic approach to a patient with suspected HUS should be implemented promptly to decrease morbidity and mortality. A useful diagnostic approach for patients suspected of HUS is outlined in Figure 4. This approach relies on stepwise laboratory analysis.Recognition of TMA is the first step in the diagnostic pathway. To do so, laboratory evaluation should include a complete blood count, peripheral blood smear, reticulocyte count, LDH level, indirect bilirubin levels, haptoglobin level, a direct antiglobulin test, and a urinalysis. Once the presence of TMA is identified, evaluation of end-organ damage should commence. For the latter, it is necessary to assess renal, cardiac, pulmonary, neurologic, and gastrointestinal function. Laboratory evaluation should include a complete metabolic panel and troponin, lactate, lipase, and liver enzyme levels. Coagulation studies, including PT, aPTT, D-dimer, and fibrinogen, should be obtained to rule out DIC. The next step should be to rule out TTP by assessing ADAMTS13 activity, which would be decreased in such disease (<10%). This step is crucial, as TTP is a medical emergency that is almost always fatal if appropriate treatment with plasmapheresis is not promptly initiated.Once the diagnosis of HUS is established, the goal is to identify the underlying etiology. If the patient presents with a history of recent diarrhea, regardless of the presence or absence of blood in the stool, a detailed investigation for Shiga toxin–producing bacterial infection should be conducted with stool studies. A pneumococcal infection should always be considered in the pediatric population based on clinical presentation; thus, the workup should include nucleic acid tests or cultures for S. pneumoniae.When primary HUS is suspected, complement activation tests should be obtained (Figure 5). Low serum C3 and normal C4 levels indicate alternative complement pathway activation. Nonetheless, this is a nonspecific and nonsensitive marker, as not patients with with an overactivation of the alternative complement cascade with an of the by soluble The is to be an of complement HUS should be suspected secondary HUS, or are out (Figure there is no diagnostic test for primary HUS. The of genetic with primary HUS to increase but many or of the patients with primary HUS have an genetic workup for suspected primary HUS should include for complement mutations and other rare causes, such as genetic for children up to for and for of metabolism such as cobalamin C in younger than 1 of a genetic abnormality is not required for diagnosis or management of primary cases of HUS, and should be for appropriate diagnosis of HUS can be the TTP and can its The presence of microangiopathic hemolytic anemia and thrombocytopenia should prompt the for these and HUS clinical manifestations and laboratory markers (Figure can the of TTP usually presents later in but can in and usually presents with more severe thrombocytopenia, neurologic fever, and less kidney an ADAMTS13 activity of less than 10% its is characterized by an systemic activation of resulting in hemorrhage and Thus, coagulation studies are usually abnormal, with PT, aPTT, low fibrinogen, D-dimer, and with hemolysis less is the of HUS which has contributed to the reduction in mortality once The of to the onset of HUS in patients with suspected confirmed STEC infection is a and to morbidity affected The stool of children with a clinical of STEC infection should be for for the high-risk serotype Shiga toxin In children with and multiorgan replacement should be The replacement of red blood cells is However, platelet should be limited to patients with significant HUS are related to thrombotic patients with STEC infection, the of and has been observed to the of bloody diarrhea and increase the for HUS and such should be and the infection to follow its the patients with a pneumococcal infection should be with antibiotic to the primary HUS was with which has Often, children would with relapses or severe disease leading to or the current of treatment for primary HUS is initiating a terminal complement such as eculizumab or if kidney function is during These are antibodies complement that the of to and the of the Of the of the complement alternative pathway cascade children at for in secondary HUS there is an overactivation of the complement it is usually the trigger Thus, the of terminal in secondary HUS is and for patients who are and for whom an underlying primary HUS be prompt and appropriate the mortality for STEC-HUS is less than 5% in Such are usually attributed to neurologic seizures, or to 50% of patients may require kidney replacement during the acute phase of the 1 to 2 the hematologic manifestations usually children function 5% on and up to 50% are with some degree of kidney damage. patients with HUS secondary to STEC should to for signs of and of with is that children with HUS secondary to STEC who initially with levels and who do not to the of HUS have including the to kidney replacement and that is related to pneumococcal infections is usually with an increase in with more than requiring and a mortality of up to HUS to be progressive with of a genetic abnormality is identified, patients with primary HUS have if not on an the of treatment in patients with primary HUS improves of such may be Thus, and should always be HUS an underlying of the alternative complement pathway with an underlying genetic secondary HUS is caused by some internal or external (infection, malignancy, transplantation, drugs, autoimmune In the pediatric 90% of HUS cases are related to an STEC However, it is essential to that severe S. pneumoniae infection can also cause of children with suspected or diagnosed STEC infection is and is that develop the to recognize the different signs and symptoms of HUS as well as to initiate primary of the underlying etiology of HUS is for prompt should be for the of bacterial pathogens in children with or nonbloody diarrhea by severe abdominal pain or on the peripheral blood smear for the presence of red blood cell fragmentation helmet is necessary HUS is on of platelet count, and kidney function is to manifestations of HUS in patients with STEC on is an between and in children with HUS. Thus, is during the diarrhea phase of STEC infection, as it the of in children who develop on is to the of antibiotics in individuals with as there is a significant positive between antibiotic and the of on the of antibiotics in patients with acute bloody diarrhea or suspected STEC for patients with suspected STEC of a clinical pathway for the evaluation of patients with suspected STEC infection and HUS.