Prognostic Value of MicroRNA Profiles in Septic Patients with Rare Hereditary Anemias: Insights from a Longitudinal Cohort Study

Background: MicroRNAs (miRNAs) are small molecules that regulate gene expression and may influence the severity and progression of rare hereditary anemias. Understanding their role can support the development of targeted treatments. To our knowledge, this multicenter longitudinal cohort is among the first to characterize miRNA profiles-particularly miR-155-in pediatric patients with rare hereditary anemias presenting with sepsis, and to report exploratory translational observations relevant to gene-based modulation frameworks. Objective: This study aimed to profile miRNA expression in septic patients with rare hereditary anemias and evaluate associations with disease severity, progression, and response to gene therapy. Methods: This prospective cohort study was conducted at five medical centers in the United States and Saudi Arabia, enrolling 400 participants-200 patients with rare hereditary anemias and 200 healthy controls. Blood samples were analyzed using high-throughput sequencing and advanced bioinformatics. Randomization and blinding procedures were applied to ensure data integrity and minimize bias. Results: At baseline enrollment during septic presentation, patients exhibited significantly lower mean hemoglobin levels compared to controls (9.2 g/dL vs 12.5 g/dL, p < 0.001). Patients with hereditary anemia had significantly lower average hemoglobin levels (9.2 g/dL) compared to controls (12.5 g/dL, p < 0.001) and higher reticulocyte counts. miR-155 was upregulated 2.5-fold in affected patients (p < 0.01). These patients required an average of six transfusions annually, compared to none in the control group (p < 0.001). Thirty-five percent of patients experienced worsening anemia over time. ROC curve analysis demonstrated miR-155 as a strong diagnostic biomarker, with 85% sensitivity, 90% specificity, and an AUC of 0.97. Conclusion: miR-155 plays a key role in the progression of rare hereditary anemias in septic patients and shows potential as both a diagnostic and therapeutic target. These findings highlight opportunities for personalized, miRNA-based therapies to improve disease management and patient outcomes. No clinically evident severe vector-related adverse events were observed during follow-up. Clinical Trial Number: ECRIN-EU-TRIAL-2025-002739.