Hemolytic Uremic Syndrome The 5 Minute Pediatric Consult


	Hemolytic Uremic Syndrome

Mary B. Leonard

Database
Differential Diagnosis
Data Gathering
Physical Examination
Laboratory Aids
Therapy
Follow-Up
Common Questions and Answers
Bibliography

DATABASE

DEFINITION

The hemolytic uremic syndrome (HUS) is a heterogeneous group of similar entities defined by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS is the most common cause of acute renal failure in childhood.

Typical (shiga-toxin, diarrhea-associated) form accounts for greater than 90% of pediatric cases and is characterized by the sudden onset of hemolytic anemia, thrombocytopenia, and acute renal failure after a prodromal illness of acute gastroenteritis, usually with bloody diarrhea.
Atypical HUS (idiopathic) is a catch-all category for several variants of HUS, including recurrent HUS, inherited HUS, and HUS associated with pregnancy, oral contraceptives, cyclosporine, antitumor drugs, malignancy, and Streptococcus pneumoniae infection.

PATHOPHYSIOLOGY

Common denominator in all forms of HUS is thought to be microvascular endothelial cell injury and dysfunction.
Typical form usually starts with an infection with a shigatoxin producing Escherichia coli, most commonly E. coli 0157:H7.
Endothelial cell injury ultimately results in local intravascular coagulation and microthrombi formation with microangiopathic hemolytic anemia and thrombocytopenia.
Pathogenesis of atypical, non-epidemic HUS is not understood.

GENETICS

Atypical HUS has been reported with both autosomal dominant and autosomal recessive patterns of inheritance. The pathogenesis and genetics of inherited HUS is unknown.

EPIDEMIOLOGY

HUS has been reported throughout the world.

Typical

Typical HUS tends to occur in the summer months, and epidemics have been reported in day care centers and nursing homes.
Typical HUS occurs mainly in older infants and young children, usually between 6 months and 4 years of age.
The shigatoxin producing E. coli is found in the intestine of beef cattle. Ground beef may be contaminated throughout with shigatoxin. If the hamburger is inadequately cooked, infection may ensue.
In reported outbreaks, the frequency of bloody diarrhea has ranged from 35 to 90%.

Atypical

Atypical HUS has no seasonal variation and may occur at any age.

COMPLICATIONS

Acute colitis is usually transient.
Complications include rectal prolapse, toxic megacolon, bowel wall necrosis, intussusception, perforation, and stricture.
Pancreatic involvement may result in pancreatitis or insulin-dependent diabetes mellitus.

CNS

Most patients have mild central nervous system symptoms that include irritability, lethargy, and behavioral changes.
Major symptoms such as stupor, coma, seizures, cortical blindness, posturing, and hallucinations occur in 20 to 40% of patients.
Thrombotic or hemorrhagic stroke may occur.
The risk of seizures is associated with hyponatremia.

PROGNOSIS

Typical HUS

Improved supportive care and a better understanding of the complications of typical HUS have resulted in a decrease in mortality to an acute fatality rate of 4% to 12%.
A substantial number of patients develop renal sequelae after typical HUS, and they should be evaluated regularly for many years.
Persistence of proteinuria after 1 year is a poor prognostic sign and warrants additional evaluation.
Recurrences of HUS are exceedingly uncommon.
Chronic renal insufficiency occurs in 4% to 9%. Children who do develop end stage renal disease are good candidates for kidney transplantation.

Atypical HUS

In general, patients with atypical HUS have a substantially worse prognosis.
Neurological symptoms are seen more commonly.
Hypertension is common during the initial illness and prolonged antihypertensive treatment is required.
Recurrences have been reported both before and after renal transplantation.
In familial HUS, relapse, end-stage renal disease, and death are common.

DIFFERENTIAL DIAGNOSIS

Infectious causes such as Shigella, Salmonella, Campylobacter, Yersinia enterocolitica, C. difficile, and Entamoeba histolytica
During the gastrointestinal prodrome, it may be difficult to distinguish HUS from appendicitis, inflammatory bowel disease, diverticulosis, or intussusception.
Thrombotic thrombocytopenic purpura (TTP) shares many features with HUS.
Sepsis with disseminated intravascular coagulation may present with acute renal failure and a microangiopathic process.

DATA GATHERING

HISTORY

Question: Gastrointestinal prodrome?
Significance: Affected children with typical HUS are usually healthy before the initiation of the gastrointestinal prodrome. The diarrhea is usually watery or bloody and is associated with abdominal discomfort.

Question: Duration?
Significance: The prodrome lasts from 1 to 15 days and often improves before onset of the triad of features inherent to HUS.

PHYSICAL EXAMINATION

Pallor and petechiae
Dehydration secondary to the gastroenteritis
May have volume overload secondary to oligoanuric renal failure
Peripheral edema, congestive heart failure, and hypertension may be present.
Mild neurological changes of irritability or behavioral changes

Special Questions

Finding: Recent hamburger ingestion.
Significance: Many cases of typical HUS have been associated with inadequately cooked hamburger meat. Epidemics have been reported in fast-food restaurant customers.

Finding: Consumption of unpasteurized milk, cheese, or cider.
Significance: May contain Shiga toxins.

LABORATORY AIDS

HEMATOLOGIC

Test: CBC
Significance: The microangiopathic hemolytic anemia may be mild or severe. Leukocytosis is often seen in typical HUS.

Test: Reticulocytes
Significance: Repeated exacerbations of the hemolysis may occur for days or weeks.

Test: Blood smear
Significance: Fragmented red blood cells or schistocytes

Test: Markers of hemolysis
Significance: Elevated lactic dehydrogenase, unconjugated bilirubin, and reticulocyte count are additional evidence of ongoing hemolysis.

Test: Platelets
Significance: The thrombocytopenia may also last for days or weeks.

Test: PT-PTT
Significance: Coagulation studies usually show increased fibrin degradation products with normal prothrombin and partial thromboplastin times.

RENAL

Test: Renal function
Significance: Elevated creatinine and BUN

Test: Electrolytes
Significance: Elevated levels of potassium, phosphorus, hydrogen ion, and uric acid; decreased concentrations of sodium, calcium, and bicarbonate

Test: Urinalysis
Significance: Microscopic hematuria; varying degrees of proteinuria; macroscopic hematuria and RBC casts may be present.

GASTROINTESTINAL

Test: Electrolytes
Significance: Decreased serum potassium

Test: Liver function tests
Significance: Albumen decreased; liver function tests are usually normal.

Test: Amylase, lipase
Significance: Pancreatic involvement may result in hyperglycemia and elevated concentrations of serum amylase and lipase. Exocrine pancreatitis is difficult to evaluate since amylase and lipase are normally cleared by the kidneys.

MICROBIOLOGY

Test: Stool
Significance: All bloody stool samples should be screened for E. coli 0157:H7. Since the rate of recovery of the organism may decline rapidly after the first 6 days of illness, stool cultures should be obtained as early in the course of illness as possible. The local health department should be notified of any isolates.

Test: Verotoxins
Significance: Serologic evidence of verotoxin may be diagnostic.

IMAGING

Test: Plain film of the abdomen
Significance: Often demonstrates colonic distention. Look for free air as evidence of bowel perforation.

THERAPY

Supportive therapy
- Fluid and electrolyte
- Volume resuscitation initially
- In a euvolemic patient, fluids should provide replacement of ongoing losses with meticulous attention to urine output.
- Hyponatremia is common.
- If the patient is fluid overloaded, fluid intake should be restricted accordingly.
Dialysis
- If medical management fails to correct hypertension hyperkalemia, hyperphosphatemia, and severe metabolic acidosis, dialysis or hemofiltration may be indicated. Dialysis is required in one-half to one-third of patients.
Anemia
- Transfusion of packed red blood cells if the hemoglobin concentration falls below 6.0 to 7.0 g/dL or if there is evidence of cardiac dysfunction. The transfusions should be given slowly since blood pressure occasionally increases during transfusions.
- Platelet transfusions should be reserved for patients with active bleeding or in preparation for an invasive procedure.
- Antibiotics are not prescribed routinely because there is evidence the antimicrobials may increase verotoxin release. Antimotility agents have also been associated with more severe disease and should be avoided.
- Nutrition must be maintained and may require total parenteral nutrition if the intestine is non-functional. The degree of renal insufficiency will dictate the need for potassium and phosphorus restriction.
Specific therapy
- Therapies have not proven to be helpful: plasmapheresis, fresh frozen plasma, intravenous immunoglobulin, heparin, antibiotics, aspirin, vitamin E for typical HUS.
- Plasmapheresis has been advocated for atypical, or idiopathic HUS.

FOLLOW-UP

WHEN TO EXPECT IMPROVEMENT

Resolution is usually heralded by a rise in platelet count and a gradual decrease in the frequency of blood transfusions.
During the recovery phase patients may require folic acid and iron supplementation.
Anuria rarely lasts more than 2 weeks. In general, a longer duration of anuria is a poor prognostic feature.
Children who sustain structural neurologic damage during the acute phase of HUS may have residual impairment, but there is tremendous potential for improvement and recovery.
Pancreatic insufficiency may persist requiring long-term insulin therapy beyond resolution of the acute illness.

PREVENTION

Most cases of typical HUS can be avoided by thoroughly cooking all hamburger-containing foods. Other sources of contaminated foods include unpasteurized apple cider or milk.

COMMON QUESTIONS AND ANSWERS

Q: What are some predictors of the severity of typical HUS?
A: Predictors include an elevated white cell count, a severe gastrointestinal prodrome, anuria early in the course of illness, and age under 2 years.

Q: In a patient with atypical HUS, what is the chance other siblings will be affected?
A: If there are no other affected family members, it is not possible to determine if the patient has the familial (i.e., autosomal recessive) form of HUS. Therefore, other siblings may be at no additional risk or may have up to 25% chance of developing HUS.

Q: How many patients with gastroenteritis from E. coli 0157:H7 will develop HUS?
A: 10% to 20%

Q: What should the family tell the day care staff and neighbors?
A: If the patient has typical HUS, contacts should be informed that any episodes of gastroenteritis merit close follow-up for evidence of anemia, thrombocytopenia, and renal insufficiency. No prophylaxis is indicated. Exclusion of infected children from day care centers until two consecutive stool cultures are negative for E. coli 0157:H7 has been shown to prevent additional transmission.

ICD-9-CM 283.11

BIBLIOGRAPHY

Boyce TG, Swerdlow DL, Griffin PM. Current concepts: Escherichia coli 0157:H7 and the hemolytic-uremic syndrome. N Engl J Med 1995;333:364–368.

Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 1998;9:1126–1133.

Neuhaus TJ, Calonder S, Leumann EP. Heterogeneity of atypical haemolytic uraemic syndromes. Arch Dis Child 1997;518–521.

Siegler RL. The hemolytic uremic syndrome. Pediatr Clin North Am 1995; 42:1505–1529.

Taylor CM, Monnens LA. Advances in haemolytic uraemic syndrome. Arch Dis Child 1998;78(2):190–193.

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