Antiphosphatidylserine Immunoglobulin M and Immunoglobulin G Antibodies Are Higher in Vivax Than Falciparum Malaria, and Associated With Early Anemia in Both Species

Abstract

Background: Anemia is a major complication of vivax malaria. Antiphosphatidylserine (PS) antibodies generated during falciparum malaria mediate phagocytosis of uninfected red blood cells that expose PS and have been linked to late malarial anemia. However, their role in anemia from non-falciparum Plasmodium species is not known, nor their role in early anemia from falciparum malaria.

Methods: We measured PS immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in Malaysian patients with vivax, falciparum, knowlesi, and malariae malaria, and in healthy controls, and correlated antibody titres with hemoglobin. PS antibodies were also measured in volunteers experimentally infected with Plasmodium vivax and Plasmodium falciparum.

Results: PS IgM and IgG antibodies were elevated in patients with vivax, falciparum, knowlesi, and malariae malaria (P < .0001 for all comparisons with controls) and were highest in vivax malaria. In vivax and falciparum malaria, PS IgM and IgG on admission correlated inversely with admission and nadir hemoglobin, controlling for parasitemia and fever duration. PS IgM and IgG were also increased in volunteers infected with blood-stage P. vivax and P. falciparum, and were higher in P. vivax infection.

Conclusions: PS antibodies are higher in vivax than falciparum malaria, correlate inversely with hemoglobin, and may contribute to the early loss of uninfected red blood cells found in malarial anemia from both species.

Keywords: Plasmodium falciparum; Plasmodium knowlesi; Plasmodium malariae; Plasmodium vivax; anemia; malaria; phosphatidylserine antibodies.

Figure 1.

Phosphatidylserine (PS) immunoglobulin M (IgM; A) and immunoglobulin G (IgG; B) antibodies in healthy controls and in patients hospitalized with falciparum (Pf), vivax (Pv), knowlesi (Pk), and malariae (Pm) malaria. PS IgM and IgG antibodies were lower in controls than in patients with malaria from any Plasmodium species (P < .0001 for all comparisons). PS IgM and IgG antibodies were higher in P. vivax compared to both P. falciparum and P. knowlesi. PS IgM antibodies were higher in P. falciparum compared to P. knowlesi (P = .014).

Figure 2.

Phosphatidylserine (PS) immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in participants experimentally infected with Plasmodium falciparum (A and B) and Plasmodium vivax (C and D). A total of 23 participants in 3 study cohorts were infected with P. falciparum and included in the analysis; PS antibodies were measured at baseline, days 7–8 (prior to treatment), days 14–15, and day 20. Eight participants in one study cohort were infected with P. vivax, with PS antibodies measured at baseline and at days 8, 7, 10, and 18. P values represent difference between baseline and day 20 (P. falciparum) or day 18 (P. vivax), by Wilcoxon signed-rank test. Data are presented as median and interquartile range.

Figure 3.

Phosphatidylserine (PS) immunoglobulin M (IgM; A) and immunoglobulin G (IgG; B) antibodies at day 20 in participants experimentally infected with Plasmodium falciparum and at day 18 in participants experimentally infected with Plasmodium vivax. Data are presented as median and interquartile range.