Can vaccines cause atypical Hemolytic Uremic Syndrome (aHUS)?

Can Vaccines Trigger Atypical Hemolytic Uremic Syndrome (aHUS)?

Yes, vaccines can trigger atypical hemolytic uremic syndrome (aHUS) in genetically predisposed individuals, though this is an extremely rare occurrence. 1, 2, 3, 4

Pathophysiology and Triggers of aHUS

aHUS is a rare form of thrombotic microangiopathy (TMA) characterized by:

• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Acute kidney injury

Genetic Predisposition

• Approximately 60% of aHUS cases have detectable mutations in complement proteins 1, 5
• Common genetic mutations include:
  • Complement factor H (CFH)
  • Membrane cofactor protein (MCP/CD46)
  • Complement factor I (CFI)
  • Complement C3
  • Thrombomodulin (THBD)
  • Diacylglycerol kinase epsilon (DGKE)

Known Triggers of aHUS

Various environmental triggers can precipitate aHUS in genetically predisposed individuals:

• Infections (including H1N1, influenza A, HIV, SARS-CoV-2) 1
• Medications
• Pregnancy
• Malignancy
• Organ transplantation
• Vaccines (rare but documented) 2, 3, 4

Vaccine-Associated aHUS: Evidence

Recent evidence has documented cases of aHUS following COVID-19 vaccination:

• Case reports show both de novo and relapse aHUS occurring after mRNA vaccines (Pfizer/BioNTech) and adenoviral vector vaccines (AstraZeneca) 2
• Onset typically occurs within days (median 3 days, range 2-15 days) after vaccination 2, 3, 4
• Patients present with classic TMA features: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury 2, 3

Genetic Risk Factors in Reported Cases

Reported cases of vaccine-triggered aHUS often involve patients with:

• Multiple inherited risk factors (e.g., pathogenic variants in CFH, MCP/CD46 gene) 3
• Homozygous CFHR3/CFHR1 gene deletions 4

Risk Assessment

Despite documented cases, the overall risk appears to be extremely low:

• In a retrospective evaluation of 29 aHUS patients who received 73 COVID-19 vaccinations without complement-inhibitory treatment, none developed aHUS relapse 2
• Benefits of vaccination generally outweigh the extremely rare risk of aHUS in the general population

Clinical Approach to Suspected Vaccine-Induced aHUS

Diagnostic Workup

When aHUS is suspected following vaccination:

1. Laboratory assessment:

   • Complete blood count with peripheral smear (looking for schistocytes >1%)
   • Markers of hemolysis: LDH, haptoglobin, indirect bilirubin
   • Renal function tests
   • ADAMTS13 activity (to exclude TTP)
   • Complement studies

2. Genetic testing:

   • Next-generation sequencing of complement genes
   • Multiplex ligation-dependent probe amplification for CFH, CFHR1-5 genes

Management

If aHUS is diagnosed following vaccination:

1. Immediate treatment:

   • Complement inhibition therapy (eculizumab or ravulizumab) within 4-8 hours of diagnosis 1, 5
   • Consider plasma exchange if diagnosis is uncertain or while awaiting complement inhibitor

2. Preventive measures:

   • Meningococcal vaccination prior to or concurrent with complement inhibitor therapy 5
   • Antibiotic prophylaxis during treatment 5
   • Note: Response to meningococcal vaccination may be hampered in aHUS patients (only 50% showed protective titers in one study) 6

Recommendations for aHUS Patients Regarding Vaccination

For patients with known aHUS:

• Vaccination is generally recommended despite the small risk of relapse 2
• Monitoring is advised following vaccination:
  • Serum creatinine
  • Proteinuria
  • Hemolysis parameters (LDH, haptoglobin)
  • Blood pressure
• Patients should be educated about early symptoms of aHUS recurrence 2

Conclusion

While vaccines can rarely trigger aHUS in genetically predisposed individuals, this risk is extremely low and should not deter vaccination in the general population. For patients with known aHUS, careful monitoring after vaccination is prudent, but the benefits of vaccination typically outweigh the risks.