What is the initial investigation algorithm for a child suspected of having Hemolytic Uremic Syndrome (HUS)?

Investigation Algorithm for Suspected HUS in Children

When HUS is suspected in a child, immediately obtain a complete blood count with platelet count, peripheral blood smear for schistocytes, LDH, haptoglobin, indirect bilirubin, direct Coombs test, comprehensive metabolic panel with creatinine, and urinalysis—while simultaneously collecting stool for culture and Shiga toxin testing. 1

Initial Emergency Assessment (Within Hours)

Core Diagnostic Triad Confirmation

• Complete blood count with platelet count: Thrombocytopenia is defined as platelets <150,000/mm³ or 25% reduction from baseline 1
• Peripheral blood smear: Examine for schistocytes, burr cells, or helmet cells indicating microangiopathic hemolysis (note: absence of schistocytes should not exclude early diagnosis due to low sensitivity) 1
• Hemolysis markers:
  • Elevated LDH levels 1
  • Reduced or absent haptoglobin 1
  • Elevated indirect bilirubin 1
• Direct Coombs test: Must be negative to confirm non-immune hemolytic anemia 1
• Renal function: Serum creatinine (≥1.0 mg/dL in children <13 years indicates acute kidney injury) 1
• Urinalysis: Check for hematuria and/or proteinuria 1

Critical pitfall: Near-normal hemoglobin may indicate dehydration rather than absence of anemia—do not be falsely reassured 1

Immediate Differential Diagnosis Testing

• ADAMTS13 activity: Must be tested urgently when thrombotic microangiopathy is confirmed, as severely deficient activity (<10 IU/dL) indicates TTP requiring immediate plasmapheresis rather than HUS 1, 2

Etiologic Workup (Simultaneous with Initial Assessment)

Distinguish Typical vs Atypical HUS

For Typical (STEC-HUS) Diagnosis:

• Stool culture and Shiga toxin testing: Test for both STEC O157 culture AND Shiga toxin/genes 1, 3
• Consider distinguishing between Shiga toxin 1 and 2: stx2 is more potent and associated with higher HUS risk 3
• If stool testing is negative but HUS is present: Serologic testing for STEC (CDC-validated testing for serogroups O157 and O111) may aid in diagnosing antecedent infection 1
• Clinical history: Typical STEC-HUS appears 4-5 days after diarrhea onset; simultaneous onset of diarrhea and HUS suggests atypical HUS 1, 3

For Atypical HUS Diagnosis:

• Complement studies: C3, C4, CH50 (classical pathway), and AP50 (alternative pathway) to assess complement activation 1
• Genetic testing: Should be performed in all suspected aHUS cases through next-generation sequencing of complement genes: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB 1
• Multiplex ligation-dependent probe amplification: Of genes CFH, CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5 1
• Anti-factor H antibodies: Test for autoimmune aHUS 2

Critical caveat: 40-50% of aHUS cases have no identifiable mutation, yet can still be diagnosed with aHUS based on clinical and laboratory criteria 1

Special Population Considerations

• Infants <1 year old: Test for mutations in complement-unrelated genes (DGKE, WT1) and inborn errors of cobalamin metabolism (MMACHC) 1, 3
• Neurological symptoms present: Obtain neurological consultation, electroencephalogram (EEG), and brain MRI 1, 4

Daily Monitoring Protocol (Days 1-14)

For diagnosed or suspected STEC infection, perform daily monitoring 1:

• Hemoglobin and platelet counts 1
• Electrolytes, BUN, and creatinine 1
• Blood pressure monitoring 1
• Peripheral blood smear for red blood cell fragmentation 1

Monitoring can stop when: Platelet count begins to increase or stabilize with resolved/resolving symptoms 1

Treatment Decision Algorithm

If Atypical HUS is Suspected or Confirmed:

Initiate eculizumab within 4-8 hours of suspected aHUS diagnosis, as delays are associated with increased morbidity and mortality 5, 2

Before eculizumab administration:

• Administer quadrivalent A, C, W, Y meningococcal conjugate vaccine and B meningococcal vaccine 5
• Initiate long-term antimicrobial prophylaxis with penicillin (or macrolides for penicillin-allergic patients) for the duration of treatment 5

If Typical (STEC) HUS:

• Supportive care only: IV fluid resuscitation during the diarrhea phase reduces risk of oligoanuric renal failure 3
• Avoid antibiotics: May worsen outcomes and potentially increase HUS risk 3
• Monitor for complications: Neurological involvement occurs in 10-20% of patients and is the first cause of death 3

Common Pitfalls to Avoid

• Do not wait for all three clinical signs: Up to 50% of aHUS cases may not have hemolytic anemia, thrombocytopenia, and renal involvement clearly present at onset 1
• Do not delay treatment for genetic testing results: Genetic testing results may take months; treatment decisions for aHUS should not wait 1
• Do not assume normal platelet count rules out HUS: If platelet count obtained within 7 days after gastrointestinal illness onset is not below 150,000/mm³, consider alternative diagnoses 1, 3
• Do not overlook dehydration: Dehydration at admission is associated with increased need for dialysis in post-diarrheal HUS 3