Estimating sequestered parasite population dynamics in cerebral malaria

Abstract

Clinical investigation of malaria is hampered by the lack of a method for estimating the number of parasites that are sequestered in the tissues, for it is these parasites that are thought to be crucial to the pathogenesis of life-threatening complications such as cerebral malaria. We present a method of estimating this hidden population by using clinical observations of peripheral parasitemia combined with an age-structured mathematical model of the parasite erythrocyte cycle. Applying the model to data from 217 Gambian children undergoing treatment for cerebral malaria we conclude that although artemether clears parasitemia more rapidly than quinine, the clearance of sequestered parasites is similar for the two drugs. The estimated sequestered mass was found to be a more direct predictor of fatal outcome than clinically observed parasitemia. This method allows a sequential analysis of sequestered parasite population dynamics in children suffering from cerebral malaria, and the results offer a possible explanation for why artemether provides less advantage than might have been expected over quinine in reducing mortality despite its rapid effect on circulating parasites.

Figure 1

Schematic of erythrocytic cycle of P. falciparum malaria. The parasite grows and replicates within host erythrocytes. Forty-eight hours after invasion, the erythrocyte ruptures releasing (R) parasite progeny, which can quickly invade other erythrocytes. Initially, the infected erythrocyte circulates in the peripheral blood, but halfway through the cycle it sequesters in the microvascular and is absent from peripheral circulation. The rate of transition out of a compartment (λ_i) is the inverse of the average time spent in that compartment. Parasite death rates (μ_i) represent the effect of drug therapy as well as the background effects of immunity and natural loss.

Figure 2

Quinine and artemether parasite clearance curves. (A) Observed parasitemia (geometric mean percentage of admission value ± SE) in children treated for cerebral malaria with artemether (n = 108) or quinine (n = 109). (B) Sample of individual parasite clearance curves taken from the artemether group (the same patterns were observed in the quinine group). Data are from ref. .

Figure 3

Model predictions from parameter estimation process. (A) Comparison of averaged clinical data from Fig. 2A (circles) to the model simulations using parameters estimated from the clinical data. (B) Estimated geometric mean (±SE) sequestered parasite clearance. Data are expressed as percentage of admission value.

Figure 4

Sequestered and peripheral parasite dynamics in individual infections. Three examples of individual peripheral parasite clearance data are shown together with the corresponding model fit and predicted sequestered population dynamics. (A and B) Treated with quinine. (C) Treated with artemether.

Figure 5

Relationship between parasite density and mortality from cerebral malaria. Circulating parasites (A) and estimated sequestered parasites (B). Both are expressed as geometric means (±SE) of the number of parasites relative to 1 μl of peripheral blood.