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:

  1. Clinical evaluation:
    • History of recent gastrointestinal illness
    • Physical examination: Signs of anemia, thrombocytopenia, and renal involvement
  2. 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
  3. Stool studies (for STEC-HUS):
    • Stool culture for E. coli O157:H7
    • PCR for Shiga toxin genes
  4. Complement studies (for aHUS):
    • C3, C4 levels
    • Genetic testing for complement mutations
  5. Imaging:
    • Renal ultrasound: To assess kidney size and exclude obstruction
  6. 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
  1. What is the classic triad of symptoms in Hemolytic-Uremic Syndrome (HUS)? Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury
  2. What is the most common cause of typical HUS in children? Shiga toxin-producing Escherichia coli (STEC), particularly O157:H7
  3. What is the primary source of STEC infection leading to HUS? Contaminated food or water, particularly undercooked ground beef
  4. What are the typical gastrointestinal symptoms preceding HUS? Bloody diarrhea and abdominal pain
  5. What is the average time interval between diarrheal illness and onset of HUS? 5-7 days
  6. Which age group is most commonly affected by typical HUS? Children under 5 years old
  7. What is the primary mechanism of kidney injury in HUS? Thrombotic microangiopathy
  8. What laboratory finding indicates hemolysis in HUS? Elevated lactate dehydrogenase (LDH) levels
  9. How is thrombocytopenia defined in HUS? Platelet count <150,000/μL
  10. What is the gold standard for diagnosing STEC infection in HUS? Stool culture for E. coli O157:H7
  11. What is the role of antibiotics in the treatment of STEC-HUS? Generally not recommended, may increase risk of HUS
  12. What percentage of children with STEC-HUS require dialysis? 50-70%
  13. What is the average duration of dialysis requirement in HUS? 1-3 weeks
  14. Which neurological complication can occur in severe cases of HUS? Seizures or altered mental status
  15. What is the mortality rate of typical HUS in children? 3-5%
  16. 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
  17. Which genetic mutations are commonly associated with atypical HUS? Mutations in CFH, CFI, MCP, C3, or CFB genes
  18. 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
  19. What targeted therapy has revolutionized the treatment of atypical HUS? Eculizumab (complement C5 inhibitor)
  20. What is the long-term prognosis for children who recover from typical HUS? Generally good, but 10-30% may have residual renal dysfunction
  21. How is fluid management typically approached in the acute phase of HUS? Careful fluid restriction to avoid volume overload
  22. What is the role of renal biopsy in the diagnosis of HUS? Usually not necessary, diagnosis is typically based on clinical and laboratory findings
  23. What is the recommended follow-up period for children who have recovered from HUS? At least 5 years
  24. What long-term complications should be monitored in HUS survivors? Hypertension, proteinuria, and chronic kidney disease
  25. How does HUS affect the coagulation profile? Typically normal PT and PTT, despite low platelets
  26. 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
  27. 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
  28. What preventive measures can reduce the risk of STEC-HUS? Proper food handling, cooking meat thoroughly, and good hygiene practices
  29. How does the presence of neurological symptoms impact the prognosis of HUS? Associated with worse outcomes and increased mortality risk


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