Abstract

Severe malaria, predominantly caused by Plasmodium falciparum, progresses unpredictably from uncomplicated 
infection to life-threatening complications, including cerebral malaria, severe anemia, and metabolic acidosis. 
Immune responses varied substantially between pediatric and adult populations, influencing disease trajectory and 
clinical outcomes. Identification of reliable immune biomarkers capable of predicting progression to severe disease 
remains a critical unmet need for early intervention strategies. This review synthesized current evidence on immune 
biomarkers that predict severe malaria progression, evaluating their performance across pediatric and adult cohorts 
while examining age-dependent immunological differences that modulate predictive capacity. A comprehensive 
analysis of literature examining soluble immune mediators, cellular markers, and functional immune parameters 
associated with severe malaria progression in diverse age groups was conducted. Elevated cytokines, including 
tumor necrosis factor alpha, interleukin 6, and interleukin 10, demonstrated prognostic value but showed variable 
performance across age groups. Thrombocytopenia and parasite biomass markers, including plasma histidine-rich 
protein 2 provided complementary prognostic information. Pediatric cohorts exhibited distinct immunological 
profiles characterized by innate immune predominance and limited regulatory responses, while adults demonstrated 
enhanced adaptive immunity but increased immunopathology. Functional assays measuring phagocytic capacity and 
antibody-dependent cellular responses showed promise but required standardization. Most studies demonstrated 
methodological limitations, including small sample sizes, single time point assessments, and inadequate validation 
across diverse transmission settings. Immune biomarker panels incorporating endothelial dysfunction markers, 
inflammatory cytokines, and parasite burden indicators offered potential for risk stratification, though age-specific 
thresholds and validation in prospective clinical trials remain essential for clinical implementation.