Blockade of the terminal complement cascade using Ravulizumab in a pediatric patient with aHUS: a case report and literature review

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ESPR420
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Abstract

Hemolytic uremic syndrome (HUS) is a rare disease in pediatrics, with the annual incidence of 3 cases per 100,000 children under the age of 5. It is characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury. High lactate dehydrogenase (LDH) and undetectable haptoglobin levels confirm intravascular hemolysis. Atypical HUS (aHUS) accounts for 5-10% of all HUS cases in children. aHUS is diagnosed based on (1) no associated disease; (2) no criteria for Shigatoxin – HUS; and (3) normal serum ADAMTS13 activity > 10%. Primary aHUS is considered to be a disease of complement dysregulation. As early as the 1970s, studies have shown that patients with aHUS have low C3 plasma levels. In the last decade, research has shown that four regulatory proteins of the complement alternative pathways - complement factor H (CFH), membrane cofactor protein (MCP or CD46), factor I (CFI) and thrombomodulin (THBD) - and two proteins of the C3 convertase - C3 and factor B (CFB) - have a role in the pathogenesis of aHUS. Eculizumab is a monoclonal antibody that binds specifically to C5 and blocks its cleavage to C5a and C5b (Figure 1) and in 2011 was the first therapeutic drug approved by the FDA for the treatment of aHUS in pediatrics and adults. Ravulizumab is the first and only long-acting C5 inhibitor that gained FDA approval in October 2019 for the treatment of aHUS. This therapy has the potential to improve quality of life with reduced infusions and caregiver hospital visits as dosing is every 8 weeks in comparison to Eculizumab which is administered every 2 weeks. 

We report a pediatric case of aHUS who was treated with Eculizumab initially. Eculizumab was converted to Ravulizumab successfully without adverse effect or disease recurrence.


History

An 8-year-old female without significant past medical history who presented to ED with one week history of abdominal pain, emesis, and jaundice. 


Physical examination findings (including vital signs)

Vital signs: Tmax 37.3oC, RR 20, BP 117/83, SpO2 100%. 

Physical examination revealed scleral icterus, jaundice, scattered petechiae on hands, thighs, lower legs and feet. Few scattered ecchymosis bruises on lateral side of left upper thigh. 


Laboratory or diagnostic imaging or procedures:

On admission, patient had anemia (Hgb 5.1 g/dL), thrombocytopenia (Plt 39 x10e9/L), and acute kidney injury (serum creatinine 6.01 mg/dL). Her high LDH (3070 unit/L) and low haptoglobin (<8 mg/dL) suggested hemolysis. Low complement C3 (59 mg/dL), normal ADAMTS13 (>100%) and a negative rheumatology panel (negative for SLE and ANCA vasculitis) suggested aHUS. Genetic testing was negative for mutations in for ADAMTS13, C3, CD46, CFB, CFD, CFH, CFHR1, CFHR3, CFHR5, CFI, DGKE, PLG, or THBD. However, she is positive for MCP/CD46 haplotype and CFH-H3 haplotype. She received hemodialysis and Eculizumab was initiated promptly. Due to the risk of meningococcal disease, the patient received anti-meningococcal vaccines before initiation of Eculizumab therapy and continues to take appropriate antibiotic prophylaxis during treatment. Within 2 months of initiation of Eculizumab therapy, her anemia, thrombocytopenia and hemolysis resolved (Figure 2) and kidney function returned to normal (Figure 3). After four months of therapy, Eculizumab was converted to Ravulizumab, a long-acting C5 inhibitor. Despite low C3 and elevated CFH autoantibodies, her kidney function remains within normal range with serum creatinine 0.5-0.6 mg/dL and eGFR > 90 ml/min/1.73 m2 during treatment. She has tolerated therapy with no adverse side effects, nor recurrence of aHUS. 


Final diagnosis

The patient was diagnosed as anti-FH-associated aHUS. 


Discussion

Our case supports the notion that timely recognition of anti-FH-associated aHUS is important and that early specific therapy with immunosuppression results in favorable outcomes. It also illustrates that the blockade of the terminal complement cascade using Eculizumab holds promise for pediatric cases. Finally, Eculizumab can be safely converted to Ravulizumab with optimal longer duration of therapy in the context of aHUS. 

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University at Buffalo
University at Buffalo
D'Youville School of Pharmacy
University at Buffalo
University at Buffalo

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