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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. [ABSTRACT FROM AUTHOR]

Background: In populations pauci-immune to malaria, risk of severe malaria increases with age. This is particularly apparent in Plasmodium knowlesi malaria. However, pathophysiological mechanisms underlying knowlesi malaria, and of the age-related increase in risk of severe malaria in general, are poorly understood.Methods: In Malaysian patients aged ≥12 years with severe (n = 47) and nonsevere (n = 99) knowlesi malaria, severe (n = 21) and nonsevere (n = 109) falciparum malaria, and healthy controls (n = 50), we measured parasite biomass, systemic inflammation (interleukin 6 [IL-6]), endothelial activation (angiopoietin-2), and microvascular function, and evaluated the effects of age.Results: Plasmodium knowlesi parasitemia correlated with age (Spearman's correlation coefficient [rs] = 0.36; P < .0001). In knowlesi malaria, IL-6, angiopoietin-2, and microvascular dysfunction were increased in severe compared to nonsevere disease, and all correlated with age, independent of parasitemia. In falciparum malaria, angiopoietin-2 increased with age, independent of parasite biomass (histidine-rich protein 2 [HRP2]). Independent risk factors for severe malaria included parasitemia and angiopoietin-2 in knowlesi malaria, and HRP2, angiopoietin-2, and microvascular dysfunction in falciparum malaria.Conclusions: Parasite biomass, endothelial activation, and microvascular dysfunction are associated with severe disease in knowlesi malaria and likely contribute to pathogenesis. The association of each of these processes with aging may account for the greater severity of malaria observed in older adults in low-endemic regions. [ABSTRACT FROM AUTHOR]

Background: Pathogenesis of severe Plasmodium vivax malaria is poorly understood. Endothelial dysfunction and reduced nitric oxide (NO) bioavailability characterize severe falciparum malaria, but have not been assessed in severe vivax malaria.Methods: In patients with severe vivax malaria (n = 9), patients with nonsevere vivax malaria (n = 58), and healthy controls (n = 79), we measured NO-dependent endothelial function by using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and assessed associations with arginine, asymmetric dimethylarginine (ADMA), and hemolysis.Results: The L-arginine level and the L-arginine to ADMA ratio (a measure of L-arginine bioavailability) were reduced in patients with severe vivax malaria and those with nonsevere vivax malaria, compared with healthy controls (median L-arginine level, 65, 66, and 98 µmol/mL, respectively [P = .0001]; median L-arginine to ADMA ratio, 115, 125, and 187, respectively [P = .0001]). Endothelial function was impaired in proportion to disease severity (median RH-PAT index, 1.49, 1.73, and 1.97 in patients with severe vivax malaria, those with nonsevere vivax malaria, and healthy controls, respectively; P = .018) and was associated with the L-arginine to ADMA ratio. While the posttreatment fall in hemoglobin level was greater in severe vivax malaria as compared to nonsevere vivax malaria (2.5 vs 1 g/dL; P = .0001), markers of intravascular hemolysis were not higher in severe disease.Conclusions: Endothelial function is impaired in nonsevere and severe vivax malaria, is associated with reduced L-arginine bioavailability, and may contribute to microvascular pathogenesis. Severe disease appears to be more associated with extravascular hemolysis than with intravascular hemolysis. [ABSTRACT FROM AUTHOR]

Background: Plasmodium knowlesi causes severe malaria, but its pathogenesis is poorly understood. Retinal changes provide insights into falciparum malaria pathogenesis but have not been studied in knowlesi malaria.Methods: An observational study was conducted in Malaysian adults hospitalized with severe (n = 20) and nonsevere (n = 24) knowlesi malaria using indirect ophthalmoscopy (n = 44) and fundus photography (n = 29).Results: The patients' median age was 44 years (range, 18-74 years). No coma or deaths occurred. Photography detected retinal changes in 11 of 12 patients (92%) with severe and 14 of 17 (82%) with nonsevere knowlesi malaria. Nonspecific retinal whitening occurred in 3 (35%) and 5 (29%) patients with severe and nonsevere disease, respectively; hemorrhages in 2 (17%) and 3 (18%); loss of retinal pigment epithelium in 1 (8%) and 4 (24%); and drusen in 9 (71%) and 12 (75%). All changes were mild, with no significant differences between severe and nonsevere disease. Patients with retinal hemorrhages had lower platelet counts than those without (median, 22 vs 43 × 10(9)/L; P= .04).Conclusions: The paucity of specific retinal findings associated with disease severity in knowlesi malaria contrasts with the retinopathy of severe adult falciparum malaria with and without coma, suggesting that falciparum-like microvascular sequestration in the brain is not a major component in severe knowlesi malaria pathogenesis. [ABSTRACT FROM AUTHOR]

Background. Plasmodium knowlesi is the commonest cause of malaria in Malaysia, but little is known regarding infection during pregnancy. Methods. To investigate comparative risk and consequences of knowlesi malaria during pregnancy, we reviewed (1) Sabah Health Department malaria-notification records created during 2012-2013, (2) prospectively collected data from all females with polymerase chain reaction (PCR)-confirmed malaria who were admitted to a Sabah tertiary care referral hospital during 2011-2014, and (3) malaria microscopy and clinical data recorded at a Sabah tertiary care women and children's hospital during 2010-2014. Results. During 2012-2013, 774 females with microscopy-diagnosed malaria were notified, including 252 (33%), 172 (20%), 333 (43%), and 17 (2%) with Plasmodium falciparum infection, Plasmodium vivax infection, Plasmodium malariae/Plasmodium knowlesi infection, and mixed infection, respectively. Among females aged 15-45 years, pregnancy was reported in 18 of 124 (14.5%), 9 of 93 (9.7%), and 4 of 151 (2.6%) P. falciparum, P. vivax, and P. malariae/ P. knowlesi notifications respectively (P = .002). Three females with knowlesi malaria were confirmed as pregnant: 2 had moderate anemia, and 1 delivered a preterm low-birth-weight infant. There were 17, 7, and 0 pregnant women with falciparum, vivax, and knowlesi malaria, respectively, identified from the 2 referral hospitals. Conclusions. Although P. knowlesi is the commonest malaria species among females in Sabah, P. knowlesi infection is relatively rare during pregnancy. It may however be associated with adverse maternal and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Background: Complement-fixing antibodies are important mediators of protection against Plasmodium falciparum malaria. However, complement-fixing antibodies remain uncharacterized for Plasmodium vivax malaria. P. vivax merozoite surface protein 3α (PvMSP3α) is a target of acquired immunity and a potential vaccine candidate.Methods: Plasma from children and adults with P. vivax malaria in Sabah, Malaysia, were collected during acute infection, 7 and 28 days after drug treatment. Complement-fixing antibodies and immunoglobulin M and G (IgM and IgG), targeting 3 distinctive regions of PvMSP3α, were measured by means of enzyme-linked immunosorbent assay.Results: The seroprevalence of complement-fixing antibodies was highest against the PvMSP3α central region (77.6%). IgG1, IgG3, and IgM were significantly correlated with C1q fixation, and both purified IgG and IgM were capable of mediating C1q fixation to PvMSP3α. Complement-fixing antibody levels were similar between age groups, but IgM was predominant in children and IgG3 more prevalent in adults. Levels of functional antibodies increased after acute infection through 7 days after treatment but rapidly waned by day 28.Conclusion: Our study demonstrates that PvMSP3α antibodies acquired during P. vivax infection can mediate complement fixation and shows the important influence of age in shaping these specific antibody responses. Further studies are warranted to understand the role of these functional antibodies in protective immunity against P. vivax malaria. [ABSTRACT FROM AUTHOR]