Parasite Strain, Host Immunity, and Circulating Blood Cells with Dead Parasites: Why Predicting Malaria Parasite Clearance Is Not a Simple Task

LETTER

Hastings et al. (1) bring to our attention the potential limitation of malaria parasite clearance rates as indicators of the effectiveness of the artemisinin-based combination therapies. While their conclusions concur with earlier findings by Dogovski et al. (2), who made use of in vitro data and in vivo mathematical modeling, the mathematical models proposed by Hastings et al. are limited with respect to two key parameters, the infecting parasite strain and host immunity. Dogovski et al. (2) illustrated that not only was accounting for splenic clearance able to resolve the discrepancy between in vivo clearance curves and in vitro estimates of drug activity but also that differential rates of splenic clearance for sensitive and resistant strains were required in order to recover simulated parasite clearance curves which agreed closely with median-parasitemia-versus-time profiles from clinical patient data presented in the work of Dondorp et al. (3). Collectively, the hypothesized findings of Kay and Hodel (1) and Dogovski et al. (2) suggest that in order to assess drug effectiveness and emergence of resistance, we cannot rely solely on parasite clearance, measured by microscope, in the first few days following initial treatment. This highlights the urgent need for laboratory measures that can differentiate live and dead circulating parasites in clinical efficacy studies. Indeed, Dogovski et al. (2) have previously suggested measuring for each patient the proportion of circulating infected red blood cells with live parasites 3 h after the initial treatment and have proposed a way that current in vitro methods for performing these measures could be adapted to the field setting.

As well as the effect of the drug, host immunity is an important factor that influences parasite clearance. Hastings et al. (1) state in their text that host immunity has simply been incorporated in the model as an additional compartment to represent splenic clearance of the infected red blood cells with dead parasites (of note, the mathematical detail for this part of the model is not provided in the supplementary information). Immunity is complex, with both innate and acquired immunity having an impact on parasite clearance in a myriad of ways (as acknowledged by Hastings et al. [1]). Host immunity, as well as splenic clearance of infected red blood cells (through pitting and opsonic phagocytosis), can prevent the merozoites from reinvading the red blood cells following schizont rupture; that is, it can reduce the parasite multiplication factor at the end of the 48-h life cycle. The complexity of the human immune response to malaria is another key aspect needing refinement in mathematical models of parasite clearance to ensure accurate assessment of antimalarial drug efficacy.