Reevaluating malaria severity metrics: insights from PfHRP2-derived biomass estimates in Ghanaian children

Background: Malaria remains a major cause of morbidity and mortality in sub-Saharan Africa. Severe Plasmodium falciparum malaria is primarily driven by parasite sequestration in deep vascular tissues. Standard diagnostic tools, such as peripheral parasitaemia determination, do not always reflect the total parasite burden. Plasma Plasmodium falciparum Histidine-Rich Protein 2 (PfHRP2) level has emerged as a potential biomarker for estimating total parasite biomass, which may better reflect disease severity than peripheral parasitaemia. However, it is still unclear how PfHRP2-estimated parasite biomass varies across different clinical malaria syndromes, how well it predicts severity compared to circulating parasitaemia, and how prior antimalarial treatment influences these measures. Addressing these gaps is critical to improving severity assessment and guiding timely interventions. Methods: Data from 118 children diagnosed with cerebral malaria (CM, n = 58), severe malaria anaemia (SMA, n = 28), or uncomplicated malaria (UM, n = 32) were collected in five referral hospitals in Accra from 2012 to 2016. Total parasite burden (PTot) was estimated using PfHRP2-based biomass measurement while the circulating parasite burden (PCir) was determined from peripheral parasite density. The sequestered parasite burden (PSeq), which represent the difference between PTot and PCir, was also evaluated. Additionally, the impact of prior antimalarial treatment on parasite burden was assessed. Results: PTot and PSeq were consistently higher than PCir in severe malaria syndromes. In UM, PTot and PCir were similar, while the median PCir was lower in CM than in UM, suggesting greater sequestration in severe disease. After regaining consciousness, CM patients exhibited decreased PTot and PSeq values compared to their values at initial clinical evaluation. Higher PSeq estimates were associated with coma. Prior antimalarial treatment also reduced PCir but did not significantly change PTot. Conclusion: PfHRP2-derived total parasite biomass demonstrated a stronger association with severe malaria syndromes than peripheral parasitaemia. Accounting for prior antimalarial treatment is essential, as it may lower circulating parasite counts without affecting total biomass. Incorporating total parasite biomass assessments into clinical evaluation could enhance disease severity classification and inform timely interventions in endemic regions.