Blood-stage dynamics and clinical implications of mixed Plasmodium vivax-Plasmodium falciparum infections

Abstract

We present a mathematical model of the blood-stage dynamics of mixed Plasmodium vivax-Plasmodium falciparum malaria infections in humans. The model reproduces features of such infections found in nature and suggests several phenomena that may merit clinical attention, including the potential recrudescence of a long-standing, low-level P. falciparum infection following a P. vivax infection or relapse and the capacity of an existing P. vivax infection to reduce the peak parasitemia of a P. falciparum superinfection. We simulate the administration of antimalarial drugs, and illustrate some potential complications in treating mixed-species malaria infections. Notably, our model indicates that when a mixed-species infection is misdiagnosed as a single-species P. vivax infection, treatment for P. vivax can lead to a surge in P. falciparum parasitemia.

Figure 1

Dynamic patterns of Plasmodium vivax and P. falciparum populations in untreated mixed infections. As detailed in the text, particular ranges of parameters lead to patterns in which the two species oscillate nearly in phase with each other, with long periods in which both parasites may appear absent from the blood (A). Other ranges lead to out-of-phase oscillatory patterns, in which one species’ peak corresponds to the other’s trough (B). In A, x = y = 0, c_s = 0.001, c_n = 0.0001, s_s = s_n = 0.001; in B, x = y = 0, c_s = 0.0001, c_n = 0.01, s_s = s_n = 0.001.

Figure 2

Population dynamics of a mixed Plasmodium vivax-P. falciparum infection, in which P. vivax first appears in the blood (from relapse or superinfection) 150 days after the appearance of P. falciparum. P. falciparum stabilizes at approximately 11,600 parasites/μl prior to the appearance of P. vivax, falls to nearly sub-detectable levels following the appearance of P. vivax, then recrudesces to levels nearly three times (32,900 parasites/μl) its level prior to the appearance of P. vivax. Here, x = y = 0, c_s = 0.001, c_n = 0.01, s_s = s_n = 0.001.

Figure 3

Population dynamics of a mixed Plasmodium vivax-P. falciparum infection, given a simultaneous appearance of the species (A), and a 10-day delay in P. falciparum appearance (B). As detailed in the text, an existing P. vivax infection can reduce peak levels of a subsequent P. falciparum superinfection (here from 10,100 to 7,400 parasites/μl). Here x = y = 0, c_s = 0.001, c_n = 0.001, s_s = 0.001, s_n = 0.1.

Figure 4

A simulation of the effects of drug treatment in 2 patients with long-standing mixed-species infections, who arrive at a clinic after a month of intermittent fevers. Both patients are treated immediately, as follows: A, high Plasmodium vivax parasitemia relative to P. falciparum (35,000 versus 10,000 parasites/μl) leads to misdiagnosis as a single-species P. vivax infection. The patient is treated with mefloquine and primaquine on day 30 of the infection. P. vivax is eliminated, but mefloquine-resistant P. falciparum recrudesces once mefloquine concentration decreases below the minimum parasiticidal concentration for this resistant strain. B, high P. falciparum parasitemia relative to P. vivax (6,575 versus 720 parasites/μl) leads to misdiagnosis as a single-species P. falciparum infection. The patient is treated with quinine on day 30 of the infection. Both P. falciparum and P. vivax blood forms are eliminated but there is a relapse from P. vivax hypnozoites, following the elimination of quinine from the blood. In A, x = y = 0, c_s = 0.001, c_n = 0.01, s_s = 0.001, s_n = 0.001. In B, x = y = 0, c_s = 0.001, c_n = 0.001, s_s = 0.001, s_n = 0.01. In both A and B, drugs are given on day 30, parasite reduction ratio = 100.

Figure 5

A, an infection-history curve from the malariatherapy treatment of a neurosyphilis patient, case 271–1126 (Boyd and Kitchen7). The vertical axis shows asexual-form parasitemia from microscopy-based estimates; the horizontal axis shows days. The time course of P. vivax (solid line) and P. falciparum (dotted line) parasitemia is shown following the inoculation of a patient (8 days earlier) by the feeding of a cage of Anopheles stephensi that had fed 28 days before on a patient infectious for P. falciparum and 21 days before on a patient infectious for P. vivax. The estimated detection threshold is 10 parasitized erythrocytes/μl. 10.5-grain doses of quinine were administered on days 8 and 9. B, a similar dynamic pattern from our model, incorporating treatment on day 8 with subcurative quinine (for which the minimum parasiticidal concentration [MPC]_falciparum is reached in 2 days, the MPC_vivax in 4). Here, x = y = 0, c_s = 0.001, c_n = 0.0001, s_s = 0.0005, s_n = 0.1.