What is the difference between atypical Hemolytic Uremic Syndrome (HUS) and typical Hemolytic Uremic Syndrome (HUS)?

Distinguishing Atypical HUS from Typical HUS

The fundamental difference is that typical HUS (STEC-HUS) is caused by Shiga toxin-producing E. coli infection and represents 90% of pediatric HUS cases, while atypical HUS (aHUS) is a complement-mediated disease caused by genetic or acquired defects in the alternative complement pathway, requiring immediate treatment with complement inhibitors. 1

Etiological Differences

Typical HUS (STEC-HUS):

• Caused by infection with Shiga toxin-producing Escherichia coli (STEC), confirmed by stool testing 1, 2
• Represents approximately 90% of HUS cases in children but only 5-10% in adults 3, 2
• Follows a gastrointestinal infection with STEC, with diarrhea preceding HUS by 4-5 days 1, 2

Atypical HUS (aHUS):

• A multifactorial disease characterized by genetic or acquired (anti-CFH antibodies) anomalies affecting the alternative complement pathway 4, 1
• Represents the majority of HUS cases in adults 3
• Genetic mutations are found in 50-60% of cases, including mutations in complement regulatory proteins: factor H (20-30%), membrane cofactor protein/MCP (5-15%), factor I (4-10%), thrombomodulin (3-5%), C3 (2-10%), and factor B (1-4%) 4, 3
• Anti-factor H antibodies are present in 6-10% of patients 3
• In 40-50% of cases, no identifiable mutation or immunologic background is detected, but this does not exclude the diagnosis 4

Clinical Presentation Differences

Typical HUS:

• Diarrhea (often bloody) precedes HUS by 4-5 days 1
• Positive stool test for STEC or Shiga toxin 1, 5
• Classic triad of hemolytic anemia, thrombocytopenia, and renal impairment is usually present 5

Atypical HUS:

• Suspicion should be raised when diarrhea is absent, when the interval between diarrhea and HUS is short, or when diarrhea and HUS occur simultaneously 1
• All three clinical signs (hemolytic anemia, thrombocytopenia, renal involvement) may not always be clearly present at onset 4
• In pediatric patients, particularly newborns, aHUS may be present even if one of these three parameters is absent: thrombocytopenia, anemia, or increased creatinine levels 4, 6
• Triggers may include medications, pregnancy, malignant lesions, infections (H1N1, influenza A, HIV, SARS-CoV-2), and organ transplantation 4

Diagnostic Approach

Essential first-line tests to differentiate:

• Stool culture and PCR for Shiga toxins/E. coli O157 to confirm or exclude STEC-HUS 1, 5
• ADAMTS13 activity to exclude thrombotic thrombocytopenic purpura (TTP) 5, 6
• Complete blood count with peripheral smear showing >1% schistocytes 5
• Complement tests (C3, C4, CH50, and anti-complement antibodies) 5

For confirmed aHUS:

• Genetic testing should be performed using next-generation sequencing of complement genes (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB) 4, 5
• However, genetic testing results should NOT delay treatment initiation 1, 5

Management Differences

Typical HUS (STEC-HUS):

• Supportive treatment is the mainstay of therapy 1
• Platelet transfusions are contraindicated as they can worsen microangiopathic thrombosis 1, 5
• Most cases resolve with supportive care alone 2

Atypical HUS (aHUS):

• Immediate initiation of complement inhibitors (eculizumab or ravulizumab) is required without waiting for genetic testing results 1, 5
• Treatment should be administered for at least 6 months 1, 5
• Patients must be vaccinated against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to therapy, or receive antimicrobial prophylaxis if urgent treatment is needed 1, 7
• Long-term antimicrobial prophylaxis is required during complement inhibitor therapy 1, 6
• Eculizumab is FDA-approved for aHUS but NOT indicated for STEC-HUS 7

Prognosis Differences

Typical HUS:

• Generally favorable prognosis with supportive care 2
• Most pediatric patients recover renal function 3

Atypical HUS:

• Without treatment, 20-50% progress to end-stage renal failure at first episode 3
• Mortality can reach 2-10% at first episode 3
• 50% of patients experience relapses 3
• Risk of recurrence after discontinuation of C5 inhibitors is 10-20%, with potential for renal failure 1, 6
• Higher mortality rates occur in children than adults with aHUS 4
• Prognosis varies by genetic mutation: factor H mutations have the worst prognosis (20% mortality, 50% progress to ESRD), while MCP mutations have the best prognosis with preserved renal function in most cases 3

Critical Pitfalls to Avoid

• Do not delay eculizumab/ravulizumab therapy while awaiting genetic testing if aHUS is suspected and STEC-HUS is excluded, as genetic mutations are found in only 50-60% of cases 1, 5
• Do not administer platelet transfusions in HUS unless there is life-threatening bleeding, as they can worsen microangiopathic thrombosis 1, 5
• Do not assume typical HUS based solely on presence of diarrhea, as aHUS can be triggered by infections 4
• In transplant recipients, absence of marked thrombocytopenia or significant anemia should not exclude a TMA diagnosis 4
• When assessing renal involvement in pediatric patients, creatinine levels must be evaluated in relation to age 4, 6