Hemolytic-Uremic Syndrome in Children
Introduction to Hemolytic-Uremic Syndrome (HUS) in Children
Hemolytic-Uremic Syndrome (HUS) is a rare but severe condition characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.
- Epidemiology:
- Incidence: Approximately 1-2 cases per 100,000 children annually
- Age: Most common in children under 5 years old
- Gender: Slightly more common in females
- Classification:
- Typical HUS (STEC-HUS): Associated with Shiga toxin-producing Escherichia coli (STEC) infection
- Atypical HUS (aHUS): Associated with genetic or acquired complement dysregulation
- Etiology:
- STEC-HUS: Most commonly caused by E. coli O157:H7
- aHUS: Mutations in complement regulatory genes (e.g., CFH, CFI, MCP, C3, CFB)
- Other causes: Streptococcus pneumoniae, HIV, certain medications
Pathophysiology of HUS
HUS is characterized by endothelial cell damage leading to thrombotic microangiopathy (TMA) in small blood vessels, particularly in the kidneys.
STEC-HUS:
- Shiga toxin:
- Binds to globotriaosylceramide (Gb3) receptors on endothelial cells
- Causes direct cellular damage and apoptosis
- Inflammatory response:
- Release of pro-inflammatory cytokines
- Activation of complement system
- Thrombotic microangiopathy:
- Formation of platelet-fibrin thrombi in small vessels
- Mechanical destruction of red blood cells
- Consumption of platelets
Atypical HUS:
- Complement dysregulation:
- Mutations in complement regulatory proteins
- Uncontrolled activation of alternative complement pathway
- Endothelial damage:
- Complement-mediated injury to endothelial cells
- Exposure of subendothelial matrix
- Thrombotic microangiopathy: Similar to STEC-HUS
Clinical Presentation of HUS in Children
The clinical presentation of HUS can vary from mild to severe, with symptoms typically developing over several days.
Prodromal Phase (STEC-HUS):
- Gastrointestinal symptoms:
- Bloody diarrhea
- Abdominal pain
- Vomiting
- Fever (may be low-grade or absent)
Acute Phase:
- Hematologic manifestations:
- Pallor
- Fatigue
- Petechiae or purpura
- Renal manifestations:
- Oliguria or anuria
- Edema
- Hypertension
- Neurological manifestations (in severe cases):
- Irritability
- Seizures
- Altered mental status
Extrarenal Manifestations:
- Cardiac involvement: Myocarditis, cardiomyopathy
- Pancreatic involvement: Pancreatitis, diabetes mellitus
- Hepatic involvement: Elevated transaminases
Diagnosis of HUS in Children
Diagnosis is based on clinical presentation, laboratory findings, and exclusion of other causes of thrombotic microangiopathy.
Diagnostic Approach:
- Clinical evaluation:
- History of recent gastrointestinal illness
- Physical examination: Signs of anemia, thrombocytopenia, and renal involvement
- Laboratory tests:
- Complete blood count: Anemia, thrombocytopenia
- Peripheral blood smear: Schistocytes (fragmented red blood cells)
- Renal function tests: Elevated creatinine, BUN
- Urinalysis: Proteinuria, hematuria
- Lactate dehydrogenase (LDH): Elevated
- Haptoglobin: Decreased or undetectable
- Stool studies (for STEC-HUS):
- Stool culture for E. coli O157:H7
- PCR for Shiga toxin genes
- Complement studies (for aHUS):
- C3, C4 levels
- Genetic testing for complement mutations
- Imaging:
- Renal ultrasound: To assess kidney size and exclude obstruction
- Additional tests:
- ADAMTS13 activity (to exclude thrombotic thrombocytopenic purpura)
- Coagulation studies
Differential Diagnosis:
- Thrombotic thrombocytopenic purpura (TTP)
- Disseminated intravascular coagulation (DIC)
- Systemic lupus erythematosus (SLE)
- Malignant hypertension
- Sepsis
Management of HUS in Children
Management of HUS is primarily supportive, with specific treatments depending on the underlying cause.
General Supportive Care:
- Fluid and electrolyte management:
- Careful fluid balance to avoid volume overload
- Correction of electrolyte imbalances
- Blood pressure control:
- Antihypertensive medications as needed
- Nutritional support:
- Enteral or parenteral nutrition as appropriate
Specific Treatments:
- Renal replacement therapy:
- Indications: Severe acute kidney injury, fluid overload, electrolyte imbalances
- Modalities: Peritoneal dialysis, hemodialysis, continuous renal replacement therapy
- Transfusion support:
- Packed red blood cells for severe anemia
- Platelet transfusions only if severe thrombocytopenia with active bleeding
- Management of extrarenal complications:
- Neurological: Anticonvulsants for seizures
- Cardiac: Management of heart failure or arrhythmias
Specific Treatments for aHUS:
- Complement inhibition:
- Eculizumab: Monoclonal antibody against C5
- Ravulizumab: Long-acting C5 inhibitor
- Plasma therapy:
- Plasma exchange or plasma infusion (less commonly used since the advent of complement inhibitors)
Monitoring and Follow-up:
- Regular assessment of renal function, hematological parameters, and organ involvement
- Long-term follow-up for potential chronic kidney disease
- Genetic counseling for families with aHUS
Prognosis and Long-term Outcomes of HUS in Children
The prognosis of HUS varies depending on the underlying cause, severity of presentation, and timeliness of treatment.
STEC-HUS:
- Acute phase mortality: 1-4%
- Recovery of renal function:
- Complete recovery: 70-80% of cases
- Residual renal impairment: 20-30% of cases
- Long-term sequelae:
- Hypertension
- Proteinuria
- Chronic kidney disease
Atypical HUS:
- Historically poor prognosis, significantly improved with complement inhibitors
- Without treatment:
- Mortality: Up to 25%
- Progression to end-stage renal disease: Up to 50%
- With complement inhibitor therapy:
- Significantly improved renal outcomes
- Reduced risk of recurrence
Factors Influencing Prognosis:
- Severity of initial presentation
- Duration of oliguria/anuria
- Presence of neurological involvement
- Timely diagnosis and initiation of appropriate treatment
Long-term Follow-up:
- Regular monitoring of renal function and blood pressure
- Screening for proteinuria
- Assessment of growth and development
- Monitoring for potential recurrence (particularly in aHUS)
Hemolytic-Uremic Syndrome in Children
- What is the classic triad of symptoms in Hemolytic-Uremic Syndrome (HUS)? Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury
- What is the most common cause of typical HUS in children? Shiga toxin-producing Escherichia coli (STEC), particularly O157:H7
- What is the primary source of STEC infection leading to HUS? Contaminated food or water, particularly undercooked ground beef
- What are the typical gastrointestinal symptoms preceding HUS? Bloody diarrhea and abdominal pain
- What is the average time interval between diarrheal illness and onset of HUS? 5-7 days
- Which age group is most commonly affected by typical HUS? Children under 5 years old
- What is the primary mechanism of kidney injury in HUS? Thrombotic microangiopathy
- What laboratory finding indicates hemolysis in HUS? Elevated lactate dehydrogenase (LDH) levels
- How is thrombocytopenia defined in HUS? Platelet count <150,000/μL
- What is the gold standard for diagnosing STEC infection in HUS? Stool culture for E. coli O157:H7
- What is the role of antibiotics in the treatment of STEC-HUS? Generally not recommended, may increase risk of HUS
- What percentage of children with STEC-HUS require dialysis? 50-70%
- What is the average duration of dialysis requirement in HUS? 1-3 weeks
- Which neurological complication can occur in severe cases of HUS? Seizures or altered mental status
- What is the mortality rate of typical HUS in children? 3-5%
- What is atypical HUS, and how does it differ from typical HUS? Atypical HUS is not associated with STEC and is often due to genetic mutations in complement regulatory proteins
- Which genetic mutations are commonly associated with atypical HUS? Mutations in CFH, CFI, MCP, C3, or CFB genes
- What is the role of plasma exchange in the treatment of atypical HUS? May be beneficial in some cases, especially if CFH mutations are present
- What targeted therapy has revolutionized the treatment of atypical HUS? Eculizumab (complement C5 inhibitor)
- What is the long-term prognosis for children who recover from typical HUS? Generally good, but 10-30% may have residual renal dysfunction
- How is fluid management typically approached in the acute phase of HUS? Careful fluid restriction to avoid volume overload
- What is the role of renal biopsy in the diagnosis of HUS? Usually not necessary, diagnosis is typically based on clinical and laboratory findings
- What is the recommended follow-up period for children who have recovered from HUS? At least 5 years
- What long-term complications should be monitored in HUS survivors? Hypertension, proteinuria, and chronic kidney disease
- How does HUS affect the coagulation profile? Typically normal PT and PTT, despite low platelets
- What is the significance of ADAMTS13 activity in differentiating HUS from TTP? ADAMTS13 activity is normal or mildly reduced in HUS, severely deficient in TTP
- What is the role of kidney transplantation in HUS patients with end-stage renal disease? Effective for typical HUS, but high recurrence risk in atypical HUS without appropriate prophylaxis
- What preventive measures can reduce the risk of STEC-HUS? Proper food handling, cooking meat thoroughly, and good hygiene practices
- How does the presence of neurological symptoms impact the prognosis of HUS? Associated with worse outcomes and increased mortality risk
Further Reading
- StatPearls: Hemolytic Uremic Syndrome
- National Kidney Foundation: Hemolytic Uremic Syndrome
- UpToDate: Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (STEC-HUS) in children
- New England Journal of Medicine: Complement in Atypical Hemolytic–Uremic Syndrome
- The Lancet: Haemolytic uraemic syndrome
