Hemolytic Uremic Syndrome in Emergency Medicine 

Updated: Dec 27, 2017
Author: Audrey J Tan, DO; Chief Editor: Steven C Dronen, MD, FAAEM 

Overview

Background

Hemolytic uremic syndrome (HUS) is primarily a disease of infancy and early childhood and is classically characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. In 1955, Gasser et al first described hemolytic uremic syndrome as a self-limited illness associated with a prodrome of diarrhea that resulted in spontaneous recovery.[1] Though the description of this childhood illness has not changed significantly through the years, additional insight into the pathology and disease process have come to light recently.

Pathophysiology

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) fall into the broader category of thrombotic microangiopathies (TMA). Thrombotic microangiopathies are characterized by the involvement of widespread occlusive microvascular thromboses resulting in thrombocytopenia, microangiopathic hemolytic anemia, and variable signs and symptoms of end-organ ischemia. Though recent research has revealed that the two disease processes have underlying similarities, HUS and TTP have historically been considered two separate disease entities.

Two predominant types of HUS are identified: one type involves diarrhea (D+) and the other, D- or atypical, does not.

D+ HUS is the classic form, accounting for 95% of cases of hemolytic uremic syndrome in children. This form of HUS occurs predominantly in children and is preceded by a prodrome of diarrhea, most commonly caused by an infection by shiga-toxin producing Escherichia coli.

Specifically, E coli serotype O157:H7 has been associated with more than 80% of infections leading to HUS. The shiga-like toxin affects endothelial cells and initiates intravascular thrombogenesis. After entering the circulation via the gastrointestinal mucosa, the toxin preferentially localizes to the kidneys, inhibiting protein synthesis and eventually leading to cell necrosis or apoptosis.

Endothelial cell damage subsequently potentiates renal microvascular thrombosis by promoting activation of the blood coagulation cascade. Platelet aggregation results in a consumptive thrombocytopenia. Microangiopathic hemolytic anemia results from mechanical damage to red blood cells circulating through partially occluded microcirculation.

E coli O157:H7 is not normally found in human intestinal flora but is present in 1% of healthy cattle. Thus, meat may become contaminated during animal slaughter and processing. The most common form of transmission to children in the United States is ingestion of undercooked meat containing viable bacteria. Ingesting unpasteurized fruits and juices, coming into contact with unchlorinated water, and person-to-person transmission in daycare or long-term care facilities are alternate routes of transmission.

D- HUS accounts for the remaining 5% of cases of hemolytic uremic syndrome and its etiology, age at onset, and clinical presentations are far more varied.[2] Unlike D+ HUS, D- HUS is not preceded by an identifiable gastrointestinal infection. The pathogenesis of D- HUS has been the focus of current research and has, thus far, been associated with complement dysregulation in up to 50% of cases.[3] Specifically, mutations in complement regulatory protein factor H, factor I, or factor B or autoantibodies against factor H have all been implicated.[3] These mutations result in inability to suppress complement activation and for reasons that are not completely understood, the glomerular endothelium is particularly susceptible to these changes.

Clinically, D- HUS has been associated with various nonenteric infections, viruses, drugs, malignancies, transplantation, pregnancy, and other underlying medical conditions such as scleroderma and antiphospholipid syndrome. Infections caused by Streptococcus pneumoniae has been linked to 40% of D- HUS cases. Categories of drugs that have been most frequently associated with D- HUS include the following:

  • Anticancer molecules (mitomycin, cisplatin, bleomycin, and gemcitabine)
  • Immunotherapeutics (cyclosporine, tacrolimus, OKT3, interferon, and quinidine)
  • Antiplatelet agents (ticlopidine and clopidogrel)

Malignancies found in conjunction with HUS include prostatic, gastric, and pancreatic cancers. Familial forms of D- HUS exist but account for fewer than 3% of cases. Unlike D+ HUS, only 4.7% of D-HUS cases in the United States involve children.

In contrast to hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) presents with the classic pentad of microangiopathic hemolytic anemia, thrombocytopenia, prominent neurologic symptoms, fever and a milder form of renal failure. The pathophysiology of thrombotic thrombocytopenic purpura is different in that, as opposed to endothelial cell injury, thrombotic thrombocytopenic purpura is thought to be caused by a deficiency in the metalloprotease ADAMTS13, which is involved in the regulation of von Willebrand factor. A lack of this protein results in spontaneous platelet aggregation and the widespread deposition of platelet-rich thrombi in the microvasculature of various organs, most notably the heart, brain, and kidneys.

Current research has demonstrated that, though a deficiency of ADAMTS13 clearly diagnoses thrombotic thrombocytopenic purpura, patients with D- HUS also share this finding. Current research suggests that these two illnesses share a similar pathophysiology and may be variants of the same disease spectrum.

Epidemiology

Frequency

United States

  • The overall incidence of D+ HUS is estimated to be approximately 2.1 cases per 100,000 persons per year, with a peak incidence in children who are younger than 5 years (6.1 cases per 100,000 per year). The lowest rate is in adults aged 50-59 years (0.5 cases per 100,000 per year).[4]

  • Incidence tends to parallel the seasonal fluctuation of E coli O157:H7 infection, which peaks between June and September.[4]

  • Incidence of D- HUS in children is approximately 2 cases per year per 100,000 total population.[4]

Mortality/Morbidity

See the list below:

  • In D+ HUS, the mortality rate is between 3% and 5%. Older children and adults often have poorer prognoses. Death is nearly always associated with severe extrarenal disease, including severe central nervous system (CNS) involvement. Approximately two thirds of children with D+ HUS require dialysis.[5]

  • In cases of D- HUS, overall mortality rate approaches 26%.

Race

Hemolytic uremic syndrome has no predilection for a specific race.

Sex

Hemolytic uremic syndrome has no predilection for either sex.

Age

See the list below:

  • D+ HUS is typically observed in infants and children, especially those aged 6 months to 4 years.

  • D- HUS is variable in its age of presentation.

 

Presentation

History

See the list below:

  • Risk factors for hemolytic uremic syndrome in children include eating rare hamburger, a recent trip to a petting zoo, and visiting a nursing home relative with diarrhea.

  • Children usually present following an acute diarrheal illness. The GI prodrome typically occurs 4-6 days following onset of diarrhea and may mimic ulcerative colitis, various enteric infections, or appendicitis.

  • Diarrhea becomes hemorrhagic in 70% of cases, usually within 1-2 days of onset of diarrhea.

  • Vomiting occurs in 30-60% of cases.

  • Urine output may be reduced or absent.

  • Neurologic symptoms are observed in 33% of patients and may include irritability, seizures, or altered mental status.

Physical

See the list below:

  • Findings of hemolytic uremic syndrome reflect those of the inciting prodromal illness and the end organ in which thrombogenesis is occurring.

  • Fever occurs in 30% of cases.

  • GI bleeding is often noted.

  • GI involvement may lead to symptoms of an acute abdomen, with occasional peritonitis.

  • Cardiac involvement may lead to congestive heart failure (CHF) and arrhythmias.

  • Microinfarcts in the pancreas may cause pancreatitis or rarely, insulin-dependent diabetes mellitus.

  • Ocular involvement may lead to retinal or vitreous hemorrhages.

  • Hypertension and oliguria are typical findings consistent with renal compromise.

Causes

See Pathophysiology.

 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

  • Aspergillosis

  • Catastrophic antiphospholipid antibody syndrome (CAPS)

  • Intussusception

  • Ischemic colitis

  • Preeclampsia

  • Vasculitis

Differential Diagnoses

 

Workup

Laboratory Studies

Hemolytic uremic syndrome (HUS) is primarily a clinical diagnosis coupled with consistent laboratory findings.

HUS produces a microangiopathic hemolytic anemia with a hemoglobin level that is typically less than 8 g/dL. This is a consistent finding and is necessary to establish the diagnosis.

The hallmark of hemolytic uremic syndrome in the peripheral smear is the presence of schistocytes. These consist of fragmented, deformed, irregular, or helmet-shaped RBCs, as shown in the image below. They reflect the partial destruction of red blood cells (RBCs) that occurs as they traverse vessels partially occluded by platelet and hyaline microthrombi. The peripheral smear may also contain giant platelets. This is due to the reduced platelet survival time resulting from the peripheral consumption/destruction. A consumptive coagulopathy is typically not present.

Peripheral smear in hemolytic uremic syndrome (HUS Peripheral smear in hemolytic uremic syndrome (HUS), with findings of microangiopathic hemolytic anemia. Note schistocytes/helmet cells as well as decrease in platelets. Image courtesy of Emma Z. Du, MD.

Thrombocytopenia is noted and is typically mild to moderate in severity with platelet counts of less than 60,000 per mL. In spite of this finding, neither purpura nor active bleeding is typically seen.

Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen are within the reference ranges, thus differentiating hemolytic uremic syndrome and thrombotic thrombocytopenic purpura from disseminated intravascular coagulation (DIC).

Elevation of lactate dehydrogenase (LDH) and indirect bilirubin levels reflects intravascular hemolysis. Bilirubin rarely exceeds 2-3 mg/dL. Haptoglobin is very low, as it is consumed by free hemoglobin released by the destroyed RBC’.

Blood urea nitrogen (BUN) and creatinine measurements are markedly elevated. However, there is no correlation between the severity of anemia and the severity of the renal disease.

Other laboratory findings are as follows:

  • Urine may contain protein and RBCs

  • D-dimer and fibrinogen levels are usually within the reference range

  • The reticulocyte count should be elevated

  • Coombs test results are negative, indicating that the anemia is not immunologically mediated

  • A moderate leukocytosis may be present but rarely more than 20,000/mL

  • Plasma contains free hemoglobin that can often be observed with the naked eye; the degree correlates with the severity of the anemia

  • Bone marrow reveals erythroid hyperplasia and increased megakaryocytes

  • Blood cultures are negative in E coli –mediated disease since only the shiga-like toxin is circulating in the blood while the organisms remain in the GI lumen

  • Stool cultures typically detect shiga toxin – producing E coli

Imaging Studies

Imaging studies are not indicated for the diagnosis of hemolytic uremic syndrome unless a viscus perforation is suspected. At that point, plain films or CT will aid in the diagnosis.

 

Treatment

Emergency Department Care

ED care should focus on supportive management, correction of blood pressure elevation, blood transfusions, and if necessary, arrangement for prompt dialysis.

Avoid unnecessary use of antibiotics or antimotility agents during diarrheal illness. The use of these agents has been shown to increase the incidence of hemolytic uremic syndrome (HUS) because as motility slows, the gut is exposed to the toxins for a longer period of time. Additionally, antibiotic-induced injury to the bacterial membrane favors the acute release of large amounts of toxins. Use of antibiotics has been shown to increase the risk of full-blown HUS by 17-fold, and thus, the recommendation is to avoid its use, except in cases of sepsis.

Maintain fluid balance. In light of the diarrheal illness, fluid resuscitation is important, although one must avoid fluid overload. Watch for and treat hyperkalemia. If indicated, treat renal failure aggressively with hemodialysis.

A study of children with HUS from Shiga toxin–producing Escherichia coli (STEC-HUS) found that fluid infusion soon after diagnosis led to a significantly better short-term outcome, with a lower rate of central nervous system involvement (7.9% vs 23.7%, P = 0.06), less need for renal replacement therapy (26.3% vs 57.9%, P = 0.01) or intensive care support (2.0 vs. 8.5 days, P = 0.02), and fewer days of hospitalization (9.0 vs 12.0 days, P = 0.03). Long-term outcomes were also significantly better in terms of renal and extrarenal sequelae (13.2% vs 39.5%, P = 0.01).[6]

Treat hypertension with standard antihypertensive agents.

Plasma exchange (plasmapheresis combined with fresh-frozen plasma replacement) is currently the treatment of choice. Plasma exchange is performed daily until remission is obtained. However, because 85% of children with hemolytic uremic syndrome recover after supportive therapy alone, plasma exchange is generally reserved for the most severe cases.

Eculizumab (Soliris) is the first treatment approved by the US Food and Drug Administration (FDA) (September, 2011) for adults and children with atypical hemolytic uremic syndrome (aHUS). Approval was based on data from adults and children who were resistant or intolerant to, or receiving, long-term plasma exchange/infusion. Data also included children (aged 2 mo to 17 y) who received eculizumab with or without prior plasma exchange/infusion. Eculizumab demonstrated significant improvement in platelet count from baseline (P = 0.0001). Thrombotic microangiopathy events were reduced, and maintained or improved kidney function was also reported.[7, 8, 9]

In a study of 11 children (median age 22 months, range 11-175) with enterohemorrhagic E coli–positive HUS requiring dialysis, Pape and colleagues reported that early use of eculizumab appears to improve neurological outcome. All the study patients had seizures and/or were in a stupor or coma. Three patients died and of the surviving 8 patients, none experienced further seizures after the first dose of eculizumab. Three patients showed mild neurological impairment at discharge, while the remaining 5 showed no impairment.[10]

Consultations

Consult a hematologist and a nephrologist to help manage the case and an intensivist to admit the patient to an ICU setting, if necessary. In severe cases, consider consulting the renal transplant service if renal dysfunction persists.

 

Medication

Medication Summary

Management consists of early dialysis for acute renal failure and general supportive care, including treatment of hypertension. Eculizumab is the first treatment approved by the US Food and Drug Administration (FDA) in September 2011 for adults and children with atypical hemolytic uremic syndrome (aHUS).

Refractory cases have been treated with vincristine or cyclosporine A. Steroids are of questionable benefit, as are antiplatelet agents such as aspirin or dipyridamole. Fibrinolytic therapy is not only ineffective but it also increases the risk of bleeding. Platelet transfusions can worsen the patient's status by inducing further organ damage.

Monoclonal Antibodies, Endocrine

Class Summary

Eculizumab is a monoclonal antibody indicated for atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy; effectiveness is based on the effects on thrombotic microangiopathy and renal function. It is not indicated for patients with Shiga toxin Escherichia coli – related hemolytic uremic syndrome (STEC-HUS).

Eculizumab (Soliris)

Monoclonal blocking antibody to complement protein C5; inhibits cleavage to C5a and C5b, thus preventing terminal complement complex C5b-9, thereby preventing RBC hemolysis. Inhibits terminal complement mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

 

Follow-up

Complications

Complications of hemolytic uremic syndrome include the following:

  • Hypertension

  • Chronic renal failure

  • Neurologic dysfunction including seizures, coma, stroke, hemiparesis, and cortical blindness: Severe CNS involvement is associated with significant mortality.

  • GI involvement, including any area from the esophagus to the anus: This can include hemorrhagic colitis, bowel necrosis/perforation, or intussusception.

  • Cardiac dysfunction, possibly precipitated by uremia and fluid overload

  • Complications involving the pancreas are seen in fewer than 10% of patients and can include glucose intolerance. Frank diabetes mellitus is rare.

  • Liver complications including hepatomegaly and/or increased serum transaminases levels are not uncommon.

  • In severe cases, death may be an inevitable outcome if the disease has progressed too far prior to presentation.

Prognosis

See the list below:

  • The overall mortality rate of hemolytic uremic syndrome (HUS) is 5-15%.

  • For unknown reasons, younger children who present in the summer with the typical diarrheal prodrome tend to do better than older children who develop HUS during the colder months of the year.

  • Adults with HUS generally have a poorer prognosis than children. In one study, 14% of adults with HUS succumbed to the disease. Adults who undergo kidney transplantation because of HUS are at much higher risk of graft loss than patients undergoing transplantation for other reasons.[11]

  • With supportive care, approximately 85% of patients recover and regain normal renal function.

  • Patients with atypical HUS have a poorer prognosis.