INTRODUCTION

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Background

Hemolytic uremic syndrome (HUS) is a disease primarily of infancy and early childhood. It is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Diarrhea and upper respiratory infection are the most common precipitating factors. HUS is the most common cause of acute renal failure in children. The term HUS was first used by Gasser and coworkers in 1955, when they described an acute fatal syndrome in children that featured hemolytic anemia, thrombocytopenia, and severe renal failure.

Pathophysiology

In children, HUS often follows a prodromal infectious disease, usually diarrhea (90%) and less often an upper respiratory infection (10%). Use of antimotility drugs may increase the risk of developing HUS. The most common cause of HUS is a toxin produced by Escherichia coli serotype O157:H7. Additional agents include Shigella, Salmonella, Yersinia, and Campylobacter species. The shiga and shigalike toxins, produced by some strains of Shigella dysenteriae and E coli O157:H7, respectively, have been associated with approximately 70% of cases of HUS in children. Because of the cytotoxic activity of these toxins on vero cells, they are referred to as verotoxins. Transmission of E coli O157:H7 appears to be caused by contaminated food, such as ground beef and other cattle products that are undercooked, and unpasteurized dairy products. Food contaminated with E coli does not look, smell, or taste bad.

Person-to-person contact, as well as contamination of public water supplies, may also have a role in the transmission of this bacterium. E coli is normal flora in the gastrointestinal tracts of some healthy cattle, and children can contract it by petting a cow.

HUS is also associated with viruses, including varicella, echovirus, and coxsackie A and B, as well as other infectious agents such as Streptococcus pneumoniae and Clostridium difficile. HUS has also been associated with AIDS, cancer, and the administration of chemotherapeutic agents. Mitomycin C is the most common chemotherapeutic agent associated with HUS. Malignancies found in conjunction with HUS include prostatic, gastric, and pancreatic malignancies. Some have suggested that HUS is mediated by immune complexes. Some cases of HUS are familial, which may reflect a genetic or human leukocyte antigen (HLA)–type predisposition.

HUS is subdivided into 2 forms, depending on whether the patient has had diarrhea (D+ HUS and D- HUS). D- HUS, which accounts for 10% of HUS cases, is sometimes referred to as atypical HUS. Although it is not associated with shiga toxin-producing E coli, it is still characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure.

HUS and thrombotic thrombocytopenic purpura (TTP) represent different ends of what is probably the same disease continuum. Endothelial cell injury appears to be the primary event in the pathogenesis of these disorders. The endothelial damage triggers a cascade of events that result in microvascular lesions with platelet-fibrin hyaline microthrombi that occlude arterioles and capillaries. The platelet aggregation results in a consumptive thrombocytopenia. The epithelial damage may result from toxins released by bacteria or viruses. In TTP, the hyaline microthrombi occur throughout the microcirculation, and microvascular thromboses may be found in the brain, skin, intestines, skeletal muscle, pancreas, spleen, adrenals, and heart. On the other hand, in HUS, microthrombi are essentially confined to the kidneys. Many of the infectious agents and drugs implicated in HUS/TTP are toxic to the vascular endothelium.

Although the vascular lesions are identical in HUS and TTP, involvement of the CNS predominates in TTP. As in TTP, DIC is not found. In contrast to TTP, the pathology remains essentially localized to the kidney, where hyaline thrombi are seen in the afferent arterioles and glomerular capillaries. Thrombi are not present in other vessels, and neurologic symptoms, other than those associated with uremia, are uncommon. Hence, renal involvement is the defining feature of HUS. On gross examination, the kidneys are swollen and pale; many fleabite hemorrhages are on the surface. Vasculitis is usually absent.

More recently, attention has focused on ADAMTS13 levels, which are normal in HUS but depressed in TTP. ADAMTS13 is a Von Willebrand factor-cleaving protease and, in the future, assay for this enzyme may be useful in distinguishing between TTP and HUS.

Recurrences of HUS have been reported, and they are noted to have a mortality rate of 30%.

Comparisons Between HUS, TTP, and Disseminated Intravascular Coagulation (DIC)

	HUS	TTP	DIC
Age	Children	Adults	Adults
CBC	Anemia	Anemia and thrombocytopenia	Anemia and thrombocytopenia
Peripheral smear	MAHA*	MAHA	MAHA
Clinical manifestation	Predominantly renal	Predominantly CNS	Reflects the underlying illness
Treatment	Supportive	Plasmapheresis, steroids	Heparin and blood components
Prognosis	Good	Poor	Generally poor

*MAHA = microangiopathic hemolytic anemia

Frequency

United States

HUS is characteristically a disease of young children. In individuals aged 5 years and younger, the average annual incidence is 2.65 cases per 100,000; in individuals aged 18 and younger, the average annual incidence is 0.97 cases per 100,000. Incidence tends to parallel the seasonal fluctuation of E coli O157:H7 infections, which peaks between June and September.

Mortality/Morbidity

• The mortality rate is 5-15%.
• Older children and adults have poorer prognoses.
• Approximately 85% of children recover if given supportive care.

Age

• HUS is typically observed in infants and children, especially those aged 6 months to 4 years.
• HUS is reported less often in adults than in children. Most adult patients are women who have been taking oral contraceptives, are postpartum, or are having obstetric complications (eg, preeclampsia, eclampsia).

CLINICAL

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History

• Children usually present following an acute diarrheal illness. The GI prodrome occurs a few days to a few weeks before the onset of HUS and may mimic ulcerative colitis, various enteric infections, and appendicitis.
• Risk factors for children include eating rare hamburgers, recent visits to a petting zoo, or even a nursing home visit to a relative with diarrhea.
• The clinical picture can suggest a GI bleed, as opposed to a toxic gastroenteritis, because the stool may be grossly bloody. The finding of grossly bloody stools in children is a strong indicator for E coli disease. Fever is often absent in these cases.
• Urine output is reduced or absent.
• Neurologic symptoms may be observed in some patients and may result from uremia. Seizures may occur, in some cases secondary to the development of a hypertensive encephalopathy.
• On the other hand, neurologic dysfunction is a key feature of TTP.

Physical

• Findings reflect those of the inciting prodromal illness.
• Petechiae, purpura, and fever are common.
• GI bleeding is often found.
• GI involvement may lead to symptoms of an acute abdomen, with occasional perforation.
• 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 hemorrhage.
• Hypertension and oliguria may be observed.

Causes

See Pathophysiology.

DIFFERENTIALS

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Other Problems to be Considered

Vasculitis

WORKUP

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Lab Studies

• As in TTP, HUS is primarily a clinical diagnosis coupled with consistent laboratory findings.
• HUS produces a microangiopathic hemolytic anemia (hemoglobin typically less than 8 g/dL). This is the hallmark finding and is necessary to establish the diagnosis.
• • The hallmark of HUS in the peripheral smear is the presence of schistocytes. These consist of fragmented, deformed, irregular, or helmet-shaped RBCs (see Image 1). They reflect the fragmentation of RBCs that occurs as the RBCs traverse vessels partially occluded by platelet and hyaline microthrombi. The peripheral smear may also contain giant platelets. This is a reflection of the reduced platelet survival time resulting from the peripheral consumption/destruction of platelets.
  • Thrombocytopenia is present but is mild to moderate in severity, typically less than 60,000 per mL. In spite of this, there is usually no purpura or active bleeding. As with the anemia, the degree of thrombocytopenia is unrelated to the severity of the renal dysfunction.
  • Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen are within the reference ranges, thus differentiating HUS/TTP from DIC.
  • No consumptive coagulopathy is present.
• Elevation of lactate dehydrogenase (LDH) and indirect bilirubin reflects intravascular hemolysis. The bilirubin rarely exceeds 2-3 mg/dL. Haptoglobin is very low.
• Blood urea nitrogen (BUN) and creatinine are markedly elevated. However, there is no correlation between the severity of anemia and the severity of the renal disease.
• Urine, if present, may contain protein and RBCs.
• Results of DIC panel (D-dimer, fibrinogen) usually are within the reference range.
• The reticulocyte count is 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 per mL.
• There may be mild fibrinolysis with slight elevation in fibrin degradation products.
• Plasma contains free hemoglobin that can often be observed with the naked eye. The degree correlates with the severity of the anemia.
• The urine contains hemoglobin, hemosiderin, albumin, RBCs, WBCs, and casts.
• Bone marrow reveals erythroid hyperplasia and increased megakaryocytes.
• Normal stool culturing does not reveal E coli O157:H7. The laboratory order must specifically request this analysis.
• Blood cultures are negative in E coli disease.

TREATMENT

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Emergency Department Care

ED care should focus on supportive management, treatment of blood pressure elevation, blood transfusions, and admission with arrangement for prompt dialysis.

• Avoid fluid overload. Watch for and treat hyperkalemia.
• 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 HUS recover after supportive therapy alone, plasma exchange is generally reserved for the most severe cases.
• In HUS associated with diarrhea, maintain adequate fluid balance and bowel rest.
• Antibiotics are not effective except for certain forms caused by Shigella dysenteriae. In fact, antibiotic therapy may increase the risk of developing HUS in children with E coli O157:H7 colitis. Trimethoprim-sulfamethoxazole may increase verotoxin production by E coli O157:H7.

Consultations

Consult a hematologist and a nephrologist; in severe cases, consider consulting the Renal Transplant Service.

MEDICATION

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Management consists of early dialysis for acute renal failure and general supportive care, including treatment of hypertension.

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.

FOLLOW-UP

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Deterrence/Prevention

• Prevention requires a reduction in fecal soilage of meat during slaughter and processing. New regulatory standards for food processing have been introduced in the United States and have reduced the contamination of meat sold commercially. It is also essential to ensure that foods are properly cooked. An internal meat temperature in excess of 155ºF (68.3ºC) is necessary. Development of institutional standards and public education concerning proper cooking of foods are important public health measures.
• Personal hygiene measures, especially hand washing, should be followed. This is especially the case when children visit a petting zoo.
• Avoid routinely treating children with antibiotics for diarrhea. A study found that, in children younger than 10 years with E coli O157:H7 infection, the relative risk was 17.3 for developing HUS following antibiotic therapy with trimethoprim-sulfamethoxazole or a beta-lactam antibiotic.

Complications

• Hypertension
• Acute renal failure usually lasting about 2 weeks and requiring hemodialysis occurs in 55-70% of patients, but they have a favorable prognosis, and as many as 70-85% recover renal function.
• Chronic renal failure
• Neurologic dysfunction - 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 and perforation, and intussusception.
• Cardiac dysfunction, possibly precipitated by uremia and fluid overload.
• Pancreatic - Although seen in fewer than 10% of patients, can include glucose intolerance. Frank diabetes mellitus is rare.
• Liver - Finding hepatomegaly and/or increased serum transaminases levels is not uncommon.

Prognosis

• The mortality rate is 5-15%.
• 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 died.
• Cancer- and chemotherapy-associated HUS are associated with a poor prognosis, despite therapy.
• With supportive care, approximately 85% of patients recover and regain normal renal function.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to suspect HUS in a child with a recent diarrheal or upper respiratory illness who now presents with azotemia, fever, and hematologic abnormalities
• Beware of exacerbating hypertension, especially when administering fluids or blood transfusions.

Special Concerns

• HUS/TTP has been associated with pregnancy. It usually resolves with delivery, although the fetal mortality rate is high. A genetic predisposition for pregnancy-induced HUS/TTP is suspected. Distinguish this from the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).

MULTIMEDIA

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Media file 1:  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.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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Article Last Updated: Jan 11, 2007