ETIOLOGY AND EPIDEMIOLOGY

HUS is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal injury and is an important cause of acute renal failure (ARF) in children. The most common type, D+HUS, is associated with a prodromal diarrheal illness and may be sporadic, epidemic, or endemic. The disease typically occurs in children between 6 months and 4 years of age. Verotoxins (VTs) have been implicated in most D+HUS, especially the Shiga-like toxin from Escherichia coli O157:H7. VT binds to a specific globoceramide receptor on endothelial cells, producing endothelial cell injury, endothelial surface coagulation, and, in severe cases, widespread microvascular glomerular and interstitial vessel thrombosis. Contamination of meat, fruit, vegetables, and water with VT-producing E. coli is responsible for many outbreaks. VT causes hemorrhagic enterocolitis of variable severity and results in HUS in 5% to 25% of affected children. VT may be produced by other E. coli strains as well as other bacteria, such as Shigella.

HUS presenting without a prodrome of diarrhea (D-HUS) may occur at any age. More cases of D-HUS related to specific strains of Streptococcus pneumoniae infections are being recognized. Other cases of D-HUS have a genetic component (often autosomal recessive) and relapsing nature. Rare familial forms of HUS have been associated with abnormalities of complement factor H, plasminogen-activator inhibitor-1, and other molecules involved in the regulation of intravascular clotting and anticoagulation.

CLINICAL MANIFESTATIONS

Classic D+HUS typically begins as gastroenteritis, often bloody, followed in 7 to 10 days by weakness, lethargy, irritability, and oliguria/anuria. Physical examination reveals irritability, pallor, edema, petechiae, and occasionally hepatosplenomegaly. Dehydration is often present; however, some children have volume overload. Hypertension may be due to volume overload or renin. The diagnosis is supported by the presence of microangiopathic hemolytic anemia, thrombocytopenia, and renal involvement (hematuria, renal insufficiency). Seizures may indicate central nervous system (CNS) involvement and occur in 20% of cases.

Children without evidence of a diarrheal prodrome may have a similar microangiopathic syndrome, identified as thrombotic thrombocytopenic purpura (TTP). Children with TTP typically have predominant CNS symptoms but may also have significant renal disease, and recurrent episodes are common. Increasingly, abnormalities of von Willebrand factor processing have been identified in affected children.

DIAGNOSTIC STUDIES

Peripheral blood smear reveals schistocytes, helmet and burr cells, and fragmented erythrocytes, (intravascular hemolysis). Evidence for disseminated intravascular coagulation is rarely present. The reticulocyte count is elevated and plasma haptoglobin is low. Coombs test is negative. Leukocytosis is common. Urinalysis typically reveals hematuria, proteinuria, and casts. Stool can be cultured to identify VT-producing E. coli strains. Tests for demonstration of VT in stool are now also available. Diarrhea and the presence of toxin-producing E. coli may have resolved by the time HUS is diagnosed.

TREATMENT AND PROGNOSIS

Therapy for HUS is supportive and includes volume repletion, control of hypertension, and early dialysis when indicated. Red blood cell transfusions are provided as needed but platelet transfusions are beneficial only during active hemorrhage. Antibiotics for the prodromal diarrhea may increase the risk of developing HUS. Antidiarrheal agents prolong exposure to VT-producing bacteria and should be avoided. Most children (>95%) survive the acute phase; more than 50% recover normal renal function. D+HUS has the best prognosis. D-HUS, familial cases, and sporadic HUS have poorer outcomes.