Abstract
BackgroundIn falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible. The peripheral blood parasite count measures only the circulating, relatively non-pathogenic parasite numbers. P. falciparum releases a specific histidine-rich protein (PfHRP2) into plasma. Quantitative measurement of plasma PfHRP2 concentrations may reflect the total parasite biomass in falciparum malaria.Methods and FindingsWe measured plasma concentrations of PfHRP2, using a quantitative antigen-capture enzyme-linked immunosorbent assay, in 337 adult patients with falciparum malaria of varying severity hospitalised on the Thai–Burmese border. Based on in vitro production rates, we constructed a model to link this measure to the total parasite burden in the patient. The estimated geometric mean parasite burden was 7 × 1011 (95% confidence interval [CI] 5.8 × 1011 to 8.5 × 1011) parasites per body, and was over six times higher in severe malaria (geometric mean 1.7 × 1012, 95% CI 1.3 × 1012 to 2.3 × 1012) than in patients hospitalised without signs of severity (geometric mean 2.8 × 1011, 95% CI 2.3 × 1011 to 3.5 × 1011; p < 0.001). Parasite burden was highest in patients who died (geometric mean 3.4 × 1012, 95% CI 1.9 × 1012 to 6.3 × 1012; p = 0.03). The calculated number of sequestered parasites increased with disease severity and was higher in patients with late developmental stages of P. falciparum present on peripheral blood smears. Comparing model and laboratory estimates of the time of sequestration suggested that admission to hospital with uncomplicated malaria often follows schizogony—but in severe malaria is unrelated to stage of parasite development.ConclusionPlasma PfHRP2 concentrations may be used to estimate the total body parasite biomass in acute falciparum malaria. Severe malaria results from extensive sequestration of parasitised erythrocytes.
Highlights
Histidine-rich protein 2 (PfHRP2) is a 30-kDa protein produced by Plasmodium falciparum [1,2]
In falciparum malaria sequestration of erythrocytes containing mature forms of Plasmodium falciparum in the microvasculature of vital organs is central to pathology, but quantitation of this hidden sequestered parasite load in vivo has not previously been possible
In a recent study we measured PfHRP2 quantitatively in synchronized P. falciparum cultures, and showed that approximately 89% of PfHRP2 is liberated at schizont rupture and that the variation in the amount released is limited [8]
Summary
Histidine-rich protein 2 (PfHRP2) is a 30-kDa protein produced by Plasmodium falciparum [1,2]. Peripheral blood parasitaemia is very widely used to assess disease severity in malaria, but it is only a weak predictor of mortality in falciparum malaria, as the less pathogenic circulating stages can be counted whereas the more pathogenic sequestered mature parasitised erythrocytes are not seen and not counted by the microscopist These sequestered parasites secrete PfHRP2 into the plasma, and PfHRP2 is liberated at schizont rupture. In the current study we quantified plasma PfHRP2 concentrations in patients with falciparum malaria and, using a simple mathematical model, applied this approach to estimate the total body parasite biomass. We related this to parameters of disease severity and outcome. An indirect measure of the number of unseen parasites in the body is a protein, PfHRP2, which the parasites produce and which is released into the blood when the red blood cells split
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