Case Study: Is 1 Month Too Young for Eculizumab?

Published on in Nephrology Update

Presentation

A 28-day-old female presented with three episodes of gross hematuria and hypertension. Atypical hemolytic uremic syndrome (aHUS) was suspected based on anemia with schistocytes, thrombocytopenia, low C3, and acute kidney injury requiring peritoneal dialysis. A septic workup initiated for hypothermia and respiratory failure was negative.

She was started on plasma therapy, but showed no improvement after 6 days. Therefore, the decision was made to start eculizumab. Despite being < 6 weeks old, she was vaccinated with pneumococcal-13 conjugate, meningococcal (groups C and Y) polysaccharide, and Haemophilus b tetanus toxoid conjugate vaccines and started on penicillin prophylaxis.

After 1 dose of eculizumab 300 mg, dialysis was discontinued and her hematological parameters improved. Genetic testing revealed a missense mutation in factor H (exon 22) and a variant of unknown significance (exon 8). At 12 months of age, she is maintained on eculizumab 300 mg every 3 weeks and penicillin prophylaxis without recurrence of aHUS or any infectious complications. Her serum creatinine concentration is 0.2 mg/dL and she has no proteinuria and normal blood pressure.

Discussion

Eculizumab is approved to treat aHUS, but because it inhibits formation of the membrane attack complex, patients are at risk for infections from encapsulated bacteria. Patients receiving eculizumab require vaccination and/or antibiotic prophylaxis against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenza.

Although eculizumab is approved for children, little is known about the dosing schedule in those < 5 kg and the infectious risk of treating very young patients, who have an inherently high risk of infection.

Prior to our patient, only two reports have described the use of eculizumab in neonates with aHUS. Due to the limited evidence regarding stopping therapy in young children, we currently favor life-long therapy for our patient despite associated risks. Risks include immunosuppression, the need for prophylactic antibiotics, repeated vascular access in a population potentially at high risk for chronic kidney disease, and the high costs of therapy — at least $125 000 a year. Some have supported liver transplantation as a curative option for aHUS, but the risks and benefits of this procedure need to be considered on a case-by-case basis.

In neonates with aHUS, we support using eculizumab with simultaneous initiation of antibiotic prophylaxis. The manufacturer recommends vaccination occur within two weeks of starting eculizumab. We recommend vaccines against pneumococcus, meningococcus (serotypes ACYW135), and Haemophilus influenzae type b that are approved in the United States for infants ≥ 6 weeks of age (see Vaccine and Antibiotic Recommendations below).

Because available neonatal meningococcal vaccines do not cover all disease-causing serotypes, we support continuing penicillin prophylaxis indefinitely. While our case supports a maintenance dosing regimen of 300 mg every 3 weeks, more research is needed to determine the most cost-effective dosing, frequency, and duration of therapy in the smallest patients.

Vaccine and antibiotic recommendations for children receiving eculizumab

Meningococcal vaccinations available for children (United States) and dosing:

  • Hib-MenCY:
    • ≥ 6 weeks of age, four-dose series at 2, 4, 6, and 12-15 months of age
  • MenACWY-CRM:
    • ≥ 2-7 months of age, four-dose series at 2, 4, 6, and 12 months of age
    • ≥ 7-23 months of age, two-dose series three months apart with 2nd dose given at >12 months of age
  • MenACWY-D:
    • ≥ 9 months of age, two-dose series three months apart

In children, we recommend indefinite antibiotic prophylaxis during eculizumab treatment and meningococcal, pneumococcal, and Haemophilus b immunizations in patients >6 weeks.

Prophylaxis options and dosing:

  • Ampicillin: 50 mg/kg/dose IV every 24 hours, maximum 1,000 mg/dose
  • Penicillin VK: < 5 years of age, 125 mg PO twice daily; ≥ 5 years of age, 250 mg twice daily
  • Amoxicillin: 20 mg/kg/day PO divided 1-2 times daily, maximum 500 mg/day
  • Erythromycin: (if penicillin allergic), < 3 years of age, 125 mg PO twice daily; ≥ 3 years of age, 250 mg PO twice daily