Real- World Use of Complement Inhibitor Therapy in Critically Ill Children With Thrombotic Microangiopathy: Results From the Spanish Multicenter Matucip Registry.

Technical Summary: Real-World Use of Complement Inhibitor Therapy in Critically Ill Children With Thrombotic Microangiopathy

Problem Statement
Thrombotic microangiopathies (TMA) are a heterogeneous group of disorders characterized by vascular endothelial injury, microangiopathic hemolytic anemia, thrombocytopenia, and ischemic organ damage. While complement inhibitor therapy (specifically anti-C5 monoclonal antibodies like eculizumab and ravulizumab) is the established first-line treatment for suspected complement-mediated hemolytic uremic syndrome (CM-HUS), its use in other TMA subtypes (e.g., infection-associated or secondary TMA) remains off-label. Although these agents are increasingly utilized in severe or refractory cases based on the hypothesis that complement activation amplifies endothelial damage, evidence regarding their application in the acute intensive care setting is limited. Existing literature primarily focuses on medium-to-long-term outcomes in specific subgroups, leaving a gap in understanding the real-world utilization patterns, timing of administration, and acute clinical course of these therapies in critically ill pediatric patients admitted to the Pediatric Intensive Care Unit (PICU).

Methodology
This study is a retrospective observational analysis utilizing data from the MATUCIP registry, a multicenter database encompassing 20 PICUs across Spain. The study population consisted of 40 pediatric patients (aged >1 month) admitted to the PICU between January 2017 and December 2025 with a diagnosis of TMA who received complement inhibitor therapy.

• Data Collection: Variables included demographic data, clinical manifestations, laboratory parameters (hemolysis markers, platelet count, kidney function), and treatment details (drug type, dosage, timing relative to diagnosis).
• Definitions: TMA diagnosis required the presence of microangiopathic hemolytic anemia and thrombocytopenia, with or without acute kidney injury. Patients were stratified into subtypes: CM-HUS, infection-associated TMA (predominantly STEC-HUS), and secondary TMA.
• Analysis: Statistical comparisons between CM-HUS and non-CM-HUS groups were performed using non-parametric tests (Mann-Whitney U, Kruskal-Wallis) and chi-square or Fisher's exact tests for categorical variables. The study was designed as descriptive and exploratory, with no formal primary outcome defined for hypothesis testing.

Key Contributions and Results
The study characterizes the clinical landscape of complement inhibitor use in a real-world PICU setting, revealing the following key findings:

• Patient Demographics and Subtypes: Of the 40 patients analyzed, 50% (20/40) were diagnosed with suspected CM-HUS. The remaining 50% received off-label therapy: 40% (16/40) had infection-associated TMA (mostly STEC-HUS), and 10% (4/40) had secondary TMA (associated with SLE, HSCT, or cyclosporin use).
• Therapeutic Patterns: Eculizumab was the predominant agent (82.5%), followed by ravulizumab (15%). The median time from diagnosis to treatment initiation was 3 days (IQR 1–5).
• Comparative Outcomes (CM-HUS vs. Non-CM-HUS):
  • Timing: Patients with suspected CM-HUS initiated treatment significantly earlier (median 2 days) compared to non-CM-HUS patients (median 4.5 days; p=0.003).
  • Clinical Severity: Non-CM-HUS patients exhibited a significantly higher rate of extrarenal manifestations (95% vs. 50%; p=0.003), specifically encephalopathy and respiratory involvement.
  • Resource Utilization: The non-CM-HUS group had longer PICU stays (median 21 days vs. 9 days; p=0.003) and required longer durations of continuous kidney replacement therapy (CKRT) (median 14 days vs. 5 days; p=0.002).
  • Sequelae: At discharge, the non-CM-HUS group had a higher incidence of hypertension (95% vs. 58%; p=0.019).
• Overall Outcomes: Kidney replacement therapy was required in 72.5% of the cohort, with CKRT being the dominant modality. The overall mortality rate was 5% (2 patients). No serious adverse effects related to the complement inhibitors were reported.

Significance and Claims
The authors position this work as the first multicenter study to specifically evaluate the use of complement inhibitors in pediatric TMA patients within the PICU setting and to analyze their short-term clinical course. The study highlights that in real-world practice, half of the patients receiving these potent therapies do so for off-label indications, reflecting the diagnostic uncertainty and clinical urgency often present in critically ill children.

The paper claims that the significant delay in treatment initiation for non-CM-HUS patients compared to CM-HUS patients suggests that off-label use often functions as a "rescue strategy" following clinical deterioration or lack of response to conventional therapy, rather than a primary diagnostic-driven intervention. The authors conclude that while these agents are frequently employed beyond approved indications due to the severity of the disease and the lack of equally effective alternatives, the heterogeneity of the non-CM-HUS group and the lack of standardized indications underscore the need for further research to rigorously evaluate efficacy and safety in these specific subtypes. The study does not claim to prove the efficacy of off-label use but rather documents its prevalence and the distinct clinical trajectories of patients receiving it compared to those with confirmed CM-HUS.