AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hemolytic-uremic syndrome (HUS) was first described in 1955. HUS consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Since 1955, thousands of cases have been reported, and HUS has been recognized as the most common cause of acute renal failure in the pediatric population.

The clinical course of HUS can vary from subclinical to life threatening. Studies have revealed distinct subgroups of HUS and have identified several etiologies for the disease. HUS is classified as diarrhea-associated (D⁺ HUS) and non–diarrhea-associated (D^- HUS). The distinction is important because the clinical courses and prognoses differ for each category.

Pathophysiology

Classic D⁺ HUS is usually preceded by a colitis caused by Shiga toxin–producing Escherichia coli (STEC). Subsequent inflammation of the colon facilitates systemic absorption of the Shiga toxin (Stx) and lipopolysaccharide (LPS) from the gastrointestinal tract. The major toxins that cause HUS, Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2), are similar in structure to the classic Stx. These toxins bind to globotriaosylceramide (Gb3), a glycolipid receptor molecule on the surface of endothelial cells in the gut, kidney, and occasionally other organs. Differential expression of Gb3 on glomerular capillaries compared with other endothelial cells may explain the predominance of renal injury. Damaged endothelial cells of the glomerular capillaries release vasoactive and platelet-aggregating substances. The endothelial cells swell, and fibrin is deposited on the injured vessel walls.

Swelling and microthrombi formation within the glomerular capillaries produce a localized intravascular coagulopathy. The glomerular filtration rate is reduced, and renal insufficiency ensues. Erythrocytes are damaged and fragmented as they traverse the narrowed glomerular capillaries. This leads to the characteristic microangiopathic hemolytic anemia. Hemolysis also may be a result of lipid peroxidation.

Thrombocytopenia is believed to result from a combination of platelet destruction, increased consumption, sequestration in the liver and spleen, and intrarenal aggregation. Platelets are damaged as they pass through the affected glomerular capillaries. Remaining platelets circulate in a degranulated form and show impaired aggregation. Stx also binds to activated platelets.

Abnormalities of anti–platelet-aggregating agents (eg, prostaglandin I₂ [PGI₂]), platelet-aggregating agents (thromboxane A₂ [TXA₂]) and von Willebrand factor (vWF) multimers are also important factors that contribute to thrombocytopenia. A decrease in PGI₂ during the early stages of HUS has been noted. Defective PGI₂ production is believed to play a role in D⁺ HUS; abnormal PGI₂ synthesis is believed to play a role in D^- HUS.

TXA₂ levels are increased during the acute stage of HUS, leading to increased platelet aggregation. Another possible cause for increased platelet aggregation is large vWF multimers. In vitro, these large multimers have a greater ability to aggregate platelets than the smaller multimers found in normal plasma. A degrading factor in normal plasma has the ability to convert the large multimer into smaller multimers. Although genetic or acquired defects in this protease have been linked to hereditary or sporadic cases of atypical HUS, alterations in the activity of this vWF protease are not involved in the pathogenesis of D⁺ HUS.

WBCs are usually elevated in the blood of patients with HUS. Activated neutrophils are believed to damage endothelial cells by releasing elastase (a catabolic enzyme that promotes endothelial cell detachment) and by producing free radicals. Monocytes may be stimulated to release cytokines (ie, interleukin-1 and tumor necrosis factor [TNF]) that also damage endothelial cells.

In cases of HUS caused by Streptococcus pneumoniae, the bacteria produce neuraminidase, which damages endothelial cells. The bacteria remove N-acetylneuraminic acid from cell-surface glycoproteins and expose the normally hidden T antigen (Thomsen-Friedenreich antigen) on erythrocytes, platelets, and glomeruli. Serum has anti-T immunoglobulin M (IgM), which can react with the antigen and cause damage to red blood cells and the kidneys.

HUS has several genetic forms. Genetically induced cases usually are not preceded by diarrheal illness, often manifest a recurrent course, and are associated with a more guarded long-term prognosis regarding maintenance of normal kidney function. The best-studied genetic variant of HUS involves mutations in one of the short consensus repeat segments of the gene for factor H, a protein that regulates complement.

Frequency

United States

Between 1982-2002, 354 E coli O157:H7–associated HUS cases were reported. Transmission route was highest among swimming outbreaks, followed by person-to-person, unknown, animal contact, foodborne, and drinking water–related outbreaks. Daycare centers were the most common person-to-person outbreak setting. Although contaminated ground beef was the most common cause of foodborne outbreaks, produce-associated outbreaks are also common (ie, lettuce, sprouts, cabbage, apple cider, apple juice). Incidence is increased during the summer and early fall. Outbreaks of diarrhea followed by HUS have been reported in institutions, boarding schools, and daycare centers. Seasonal variation is not observed in D^- HUS.

International

HUS occurs worldwide but has a higher incidence in South Africa, Holland, and Argentina.

Mortality/Morbidity

Mortality rates have decreased progressively from near universal fatality in 1955 to only 3-5% during the 1990s. This improvement is attributed to better management of hypertension and acute renal failure during the acute stage of the disease, with use of preemptive dialysis. The mortality rate in underdeveloped countries remains as high as 72%. Patients with hereditary HUS have a worse prognosis. Mortality rates are greater than 90% in patients with autosomal dominant disease and 70% in patients with the autosomal recessive form.

Race

HUS occurs in all races; however, it is very rare in blacks. This observation has no explanation.

Sex

Males and females are affected in equal numbers; however, the disease may affect female patients more severely.

Age

D⁺ HUS usually occurs in children aged 7 months to 6 years. No age predilection exists for D^- HUS.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

D⁺ HUS: Patients experience several days of diarrhea, with or without vomiting, followed by sudden onset of symptoms such as irritability and pallor. In more than 80% of patients, the diarrhea is evidently bloody. Other symptoms include restlessness, oliguria, edema, and macroscopic hematuria. In some patients, the prodrome may improve as HUS symptoms begin. The clinical picture may mimic that of an acute abdomen. In patients infected with a Shiga toxin–producing strain of E coli, HUS occurs in 5-15%. The risk of progression to HUS is increased in very young or elderly persons, in patients who have been treated with antimotility drugs or antibiotics, and in patients with a fever or a high leukocyte count.

D^- HUS may follow a respiratory illness but usually does not follow a prodromal illness.

Features of HUS are as follows:

• Hematology
• • Hemolysis occurs in all patients with HUS. It can proceed rapidly, resulting in a rapid fall of the hematocrit.
  • Platelet counts usually fall below 40,000/mm³. However, the degree of thrombocytopenia does not correlate with the severity of HUS, and some children can maintain relatively normal kidney function despite severe hematologic abnormalities.
  • Many patients have petechiae, purpura, and oozing from venipuncture sites.
  • Overt bleeding is less common.
• Central nervous system
• • Patients often present with sudden onset of lethargy and irritability.
  • Other findings may include ataxia, coma, seizures, cerebral swelling, hemiparesis, and other focal neurologic signs.
  • CNS changes may be caused by cerebral ischemia from microthrombi, effects of hypertension, hyponatremia, or uremia.
  • D^- HUS tends to be associated with a greater number of neurologic symptoms than D⁺ HUS.
• Renal system
• • Acute renal insufficiency usually begins with the onset of hemolysis. Although patients have decreased urine output, frequent diffuse watery stools may mask this sign.
  • If renal insufficiency is not recognized and treated, hyponatremia, hyperkalemia, severe acidosis, ascites, edema, pulmonary edema, and hypertension ensue.
• Gastrointestinal tract: D⁺ HUS usually is preceded by 3-12 days of watery or bloody diarrhea. Vomiting and crampy abdominal pain are also common. Note that diarrhea may improve as the other HUS symptoms begin (eg, thrombocytopenia, renal insufficiency). Intestinal necrosis is a possible life-threatening complication.
• Infectious signs: Fever is present in 5-20% of patients. The presence of fever, leukocytosis, or both is a prognostic indicator of the risk of developing more severe HUS.
• Pancreas: Mild pancreatic involvement is common but can be severe on occasion, with necrosis, pseudocysts, or both, which can leave the patient with insulin-dependent diabetes and, on rare occasion, exocrine dysfunction.
• Cardiovascular: Congestive heart failure may occur.

Physical

• Blood pressure is elevated.
• Child appears ill and pale.
• Abdominal pain may be present.
• Peripheral edema may be present.
• Petechiae, purpura, or oozing from venipuncture sites may be present.

Causes

The causes of D⁺ HUS and D^- HUS differ.

• Diarrhea-associated hemolytic-uremic syndrome
• • Gastrointestinal tract infection with STEC precedes most cases of typical D⁺ HUS. Stx1 is identical to the Stx produced by Shigella dysenteriae. Stx2 has a 55-60% amino acid homology with Stx. They injure the gut and lead to hemorrhagic colitis. The majority of cases worldwide are associated with STEC 0157:H7 infection. This organism is very resilient; active disease has been reported in environments up to 10 months following initial contamination. Aside from Stx production, this bacteria produces virulence genes that mediate tight adherence to the host cell, facilitating transluminal transport of the toxins into the systemic circulation. Cattle are the major reservoir for human infection. The use of antimotility agents, antidiarrheal agents, and antibiotics has been reported to increase the risk of developing HUS.
  • Other causes of HUS include infection by the following:
    • S dysenteriae (established as an etiologic agent)
    • Salmonella typhi (established as an etiologic agent)
    • Campylobacter jejuni (established as an etiologic agent)
    • Yersinia species
    • Pseudomonas species
    • Bacteroides species
    • Entamoeba histolytica
    • Aeromonas hydrophilia
    • Organisms of the class Microtatobiotes
• Non-diarrhea–associated hemolytic-uremic syndrome
• • Inherited (autosomal dominant or recessive), eg, mutations in the gene for factor H (a complement regulatory protein)
  • S pneumoniae (neuraminidase associated)
  • Portillo virus
  • Coxsackie virus
  • Influenza virus
  • Epstein-Barr virus
  • Vaccines (eg, mumps; measles; smallpox; polio; diphtheria, pertussis, tetanus [DPT])
  • Pregnancy
  • Drugs (eg, chemotherapy, oral contraceptives)
  • Bone marrow transplantation
  • Malignancy
  • Idiopathic
  • Systemic lupus erythematosus (SLE)
  • Glomerulonephritis
  • Malignant hypertension

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Thrombotic thrombocytic purpura (TTP)
Disseminated intravascular coagulation (DIC)
Bilateral renal vein thrombosis
Henoch-Schönlein purpura
Immune hemolytic anemia and thrombocytopenia
Sepsis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Hematology
• • CBC with differential reveals thrombocytopenia, increased megakaryocytes, anemia, and elevated WBC count with a left shift (ie, immature WBCs, including bands, myelocytes, metamyelocytes).
  • Peripheral blood smear shows fragmented red blood cells (eg, schistocytes, helmet cells, burr cells).
  • Coombs test results are negative, except with S pneumoniae–associated HUS.
  • Reticulocyte count is elevated.
  • Levels of serum haptoglobin, which binds hemoglobin, are decreased.
  • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal.
  • Fibrin degradation products are increased.
  • Fibrinogen is increased or within reference range.
• Serum chemistry testing
• • BUN and creatinine levels are elevated.
  • Bicarbonate concentration is decreased.
  • Sodium concentration is decreased because of fluid overload.
  • Potassium concentration may be elevated (because of renal failure and hemolysis) or decreased.
  • Phosphorous concentration is elevated.
  • Uric acid level is increased because of acute renal failure, dehydration, and cell breakdown.
  • Protein and albumin levels are mildly decreased.
  • Bilirubin level is increased.
  • Liver enzyme levels are elevated.
  • Lactate dehydrogenase level is elevated.
  • Triglyceride levels are increased.
• Urinalysis
• • Protein
  • Heme
  • Bilirubin
  • Red blood cells (dysmorphic)
  • White blood cells
  • Casts - Cellular, granular, pigmented, hyaline
• Stool testing
• • Culture: Usually, culturing yield is low after 7 days of diarrhea. The standard method used to detect and isolate STEC involves sorbitol MacConkey (SMAC) agar plates that enable identification of characteristic sorbitol nonfermenting colonies of STEC O157:H7.
  • Stx may be detected using specific antibody testing, gene studies, and enzyme-linked immunosorbent assay (ELISA).
• Serum antibodies to STEC 0157:H7

Imaging Studies

• Obtain a chest radiograph to screen for pulmonary congestion/edema.

Other Tests

• Perform an ECG to monitor for affects of hyperkalemia.

Histologic Findings

HUS targets the kidneys. Histologic analysis reveals swollen glomerular endothelial cells. Accumulation of fibrinlike material in subendothelial space separates the glomerular endothelial cells from the basement membrane. Thrombi may be observed in the glomerular capillaries and arterioles. These findings can progress to acute cortical necrosis involving both glomeruli and convoluted tubules.

Tissue section of the gut shows microangiopathy, with endothelial cell injury, and thrombosis, with submucosal edema and hemorrhage. Microthrombi may be observed in other organs, including the lungs, liver, heart, adrenal glands, brain, thyroid, pancreas, thymus, lymph nodes, and ovaries.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Successful management begins with early recognition of the disease and supportive care. Management includes good control of volume status, electrolyte abnormalities, hypertension, and anemia.

• Treatment for acute renal failure
• • Monitor hydration status closely and frequently. This includes serial and frequent measurements of body weight, fluid intake and output, heart rate, and blood pressure.
  • Restrict fluids to insensible losses plus output.
  • Monitor electrolytes. Testing may need to be performed several times a day in the early stages of disease or while children are on dialysis. In children in whom kidney function is stable, testing may be performed daily.
  • Do not add potassium to replacement fluids unless the child is hypokalemic. If the patient develops fluid overload, diuretics, such as furosemide, may be administered.
  • Approximately 50% of patients with D⁺ HUS require a period of dialysis. Consider early dialysis if the patient develops severe fluid overload, severe hyperkalemia, severe acidosis, hyponatremia, or oligoanuria that is unresponsive to diuretics. The dialysis techniques used may be peritoneal dialysis, hemodialysis, or continuous arteriovenous hemodiafiltration.
  • In most patients, hemodialysis has no advantage over peritoneal dialysis. Peritoneal dialysis is usually well tolerated and technically easier in small infants. Some data indicate that peritoneal dialysis may be preferred because it facilitates clearance of plasminogen activator inhibitor-1 (PAI-1) and promotes more rapid recovery of renal function. When dialysis is required, it is usually needed for 5-7 days. If dialysis is not readily available, severe hyperkalemia may be treated with intravenous bicarbonate, glucose and insulin, and calcium (if ECG changes are noted). Oral or rectal Kayexalate also may be used.
• Treatment for hematologic abnormalities
• • Maintain hemoglobin level at greater than 7 g/dL. This criterion may need to be applied more stringently during the acute phase of the disease when the hematocrit may be falling rapidly and extracellular fluid volume overload may compromise pulmonary function. Later on in the disease course, transfusion may be withheld despite significant anemia if the child is hemodynamically stable.
  • Transfusion of packed red blood cells may be administered for symptomatic anemia (eg, tachycardia, orthostatic changes in blood pressure or heart rate, congestive heart failure) or if the hematocrit falls rapidly.
  • Although platelet transfusion in certain situations is controversial (since further platelet aggregation may increase thrombus formation), platelet transfusions are recommended for symptomatic bleeding and prior to surgical procedures (ie, central line placement).
  • Plasma exchange has been beneficial in patients with D^- HUS and prolonged or recurrent HUS. Avoid plasma exchange in pneumococcal or neuraminidase HUS because plasma contains antibodies to the T antigen. The presence of these antibodies worsens the hemolytic process.
• Treatment for hypertension: A wide range of antihypertensive medications are available for treatment and should be individualized on a patient-by-patient basis. ACE inhibitors should be used with caution in individuals with a decreased glomerular filtration rate (GFR) or with hyperkalemia. Treatment is covered separately in Hypertension.
• Nutritional concerns
  • Maintaining adequate energy intake enterally or parenterally is important.
  • Patients may require total parenteral nutrition (TPN) because of continued diarrhea, colitis, abdominal pain, intestinal ileus, or anorexia.
  • Lipid infusion may be limited if hypertriglyceridemia is present.

Surgical Care

No specific surgical technique is recommended; however, surgical procedures may be needed acutely if evidence exists of severe colitis, bowel necrosis, or perforation. In the chronic phase, patients may require surgery to resect intestinal strictures.

Consultations

• Nephrologist
• Hematologist/oncologist
• Cardiologist
• Neurologist
• Pulmonologist
• Social worker
• Psychologist

Diet

• Limit fluid intake to replace insensible losses and urine output.
• A low-salt high-energy diet is necessary.
• TPN may be needed.

Activity

Bedrest is necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Anticoagulant and thrombolytic therapeutic agents (eg, heparin, streptokinase, urokinase, aspirin, dipyridamole) have not been beneficial in treatment of HUS. Some physicians still use aspirin and dipyridamole in the hope of improving outcome, with the belief that these medications are not associated with severe adverse effects; however, physicians agree that these medications probably have very little clinical significance.

Corticosteroids, plasma infusions, plasmapheresis, vitamin E, furosemide, and captopril do not affect the outcome of HUS; however, antihypertensives and diuretics may be of use in controlling hypertension and fluid overload.

If patients develop seizures, administer anticonvulsants.

The use of intravenous immunoglobulin G (IgG) in one study showed faster recovery in patients with thrombocytopenia and oliguria, with a reduction in CNS sequelae. Intravenous IgG has not been shown to be effective in the treatment of familial HUS.

Antibiotic treatment for D⁺ HUS remains controversial. Several studies have shown that antibiotics may be detrimental; however, these trials were not fully randomized. To date, no large randomized studies have shown good evidence for or against the use of antibiotics in D⁺ HUS.

Drug Category: Immunoglobulin

Immunoglobin is purified preparation of gamma globulin. It is derived from large pools of human plasma and is composed of 4 subclasses of antibodies, approximating the distribution of human serum.

Drug Category: Antidotes

These agents are used in the management of poisoning, overdose, prevention of toxic effects, or metabolic disorders in which toxic substances accrue. Mechanisms of action are variable (eg, antagonists, toxin transformation, altered metabolism, chelation, directed antibodies).

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• After recovery, monitor patients for arterial hypertension and proteinuria. Persistence of hypertension or proteinuria 1 year after an episode of HUS indicates an increased risk of progression to chronic renal failure. Although recurrence of HUS has been reported, it is uncommon and suggests a genetic predisposition for the disease. Recurrence of HUS after renal transplant also has been reported.
• Check hemoglobin levels 1 month after discharge. The goal is a hemoglobin level greater than 100 g/L.
• Consider screening all survivors of D⁺ HUS for diabetes with oral glucose tolerance test at least 1 and 2 years after recovery.

In/Out Patient Meds

• Patients with persistent hypertension require antihypertensives.

Transfer

• Transfer may be required if the patient is at a facility that does not have the capability for blood product transfusions or dialysis.

Deterrence/Prevention

• Avoid ingestion of raw or undercooked meat.
• Avoid unpasteurized milk and cheese.
• Practice good hand-washing technique, especially during outbreaks of diarrhea.
• Avoid taking antidiarrheal or antimotility agents for diarrhea.

Complications

• Renal system
• • Renal insufficiency
  • Renal failure
• Central nervous system
• • Sleep-related or behavioral problems (resolve within several months of acute illness)
  • Mental retardation
  • Epilepsy
  • Focal motor deficit
  • Optic atrophy
  • Cortical blindness
  • Learning disability
• Endocrine system
• • Diabetes mellitus
  • Pancreatic exocrine insufficiency
  • Possibility of endocrine conditions persisting in patients with insulin deficiency or pancreatitis during the acute stage of HUS
  • Death
• Gastrointestinal system: Intestinal necrosis
• Cardiology: Congestive heart failure

Prognosis

• Prognosis depends on the nature of the HUS. In general, patients with D⁺ HUS have a better outcome than patients with D^- HUS.
• Diarrhea-associated hemolytic-uremic syndrome
• • Most patients with D⁺ HUS who receive the appropriate treatment have a good recovery. Poor prognostic indicators include the following:
    • Elevated WBC count at diagnosis
    • Prolonged anuria
    • Severe prodromal illness
    • Severe hemorrhagic colitis with rectal prolapse or colonic gangrene
    • Severe multisystemic involvement
    • Persistent proteinuria
  • Studies have shown that patients who recover fully have good renal function on follow-up examinations. Some studies have shown long-term reduced renal functional reserve in patients with HUS; however, these patients were able to maintain serum creatinine levels within reference range. The clinical significance of these data on long-term renal function is unknown because the longest follow-up studies have only covered 10 years. In general, if a patient has normal blood pressure and serum creatinine levels within reference range and does not have proteinuria at a 1-year follow-up examination, the long-term prognosis for preservation of renal function is good.

Patient Education

• Diet
• • Low-salt diet to decrease risk of hypertension
  • Diet high in iron and folic acid content to help recover from anemia
  • High-energy diet to help patient regain lost weight
• Social worker or psychologist consultation to help the family cope with the illness

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize the disease
• Failure to recognize and treat fluid overload
• Failure to monitor electrolytes and correct imbalances as needed
• Failure to recognize when to begin dialysis
• Treating hypertension in asthmatic patients with HUS with beta-blockers that may induce bronchospasms
• Failure to recognize and treat symptomatic anemia
• Failure to recognize and treat symptomatic thrombocytopenia

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Blaser MJ. Bacteria and diseases of unknown cause: hemolytic-uremic syndrome. J Infect Dis. Feb 1 2004;189(3):552-5. [Medline].
• Brunner K, Bianchetti MG, Neuhaus TJ. Recovery of renal function after long-term dialysis in hemolytic uremic syndrome. Pediatr Nephrol. Feb 2004;19(2):229-31. [Medline].
• Kaplan BS, Cleary TG, Obrig TG. Recent advances in understanding the pathogenesis of the hemolytic uremic syndromes. Pediatr Nephrol. May 1990;4(3):276-83. [Medline].
• Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. Jun 1998;9(6):1126-33. [Medline].
• Milford DV, Taylor CM. New insights into the haemolytic uraemic syndromes. Arch Dis Child. Jul 1990;65(7):713-5. [Medline].
• Nathan DG, Orkin SH, eds. Nathan and Oski's Hematology of Infancy and Childhood. Vol 1. 5th ed. Harcourt Health Sciences;1998:531-6.
• Pickering LK, Obrig TG, Stapleton FB. Hemolytic-uremic syndrome and enterohemorrhagic Escherichia coli. Pediatr Infect Dis J. Jun 1994;13(6):459-75; quiz 476. [Medline].
• Rangel JM, Sparling PH, Crowe C, et al. Epidemiology of Escherichia coli O157:H7 outbreaks, United States, 1982-2002. Emerg Infect Dis. Apr 2005;11(4):603-9. [Medline].
• Robson WL, Leung AK, Kaplan BS. Hemolytic-uremic syndrome. Curr Probl Pediatr. Jan 1993;23(1):16-33. [Medline].
• Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr. Apr 2005;17(2):200-4. [Medline].
• Stewart CL, Tina LU. Hemolytic uremic syndrome. Pediatr Rev. Jun 1993;14(6):218-24. [Medline].
• Trachtman H, Christen E. Pathogenesis, treatment, and therapeutic trials in hemolytic uremic syndrome. Curr Opin Pediatr. Apr 1999;11(2):162-8. [Medline].
• Varade WS. Hemolytic uremic syndrome: reducing the risks. Contemp Pediatr. 2000;17:54-64.

Article Last Updated: Jun 27, 2006