Effect of red blood cell variants on childhood malaria in Mali: a prospective cohort study

Red blood cell (RBC) variants protect African children from severe Plasmodium falciparum malaria. Their individual and interactive impacts on mild disease and parasite density, and their modification by age-dependent immunity, are poorly understood

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Relationship between malaria incidence and IgG levels to Plasmodium falciparum merozoite antigens in Malian children: impact of hemoglobins S and C.

Heterozygous hemoglobin (Hb) AS (sickle-cell trait) and HbAC are hypothesized to protect against Plasmodium falciparum malaria in part by enhancing naturally-acquired immunity to this disease. To investigate this hypothesis, we compared antibody levels to four merozoite antigens from the P. falciparum 3D7 clone (apical membrane antigen 1, AMA1-3D7; merozoite surface protein 1, MSP1-3D7; 175 kDa erythrocyte-binding antigen, EBA175-3D7; and merozoite surface protein 2, MSP2-3D7) in a cohort of 103 HbAA, 73 HbAS and 30 HbAC children aged 3 to 11 years in a malaria-endemic area of Mali. In the 2009 transmission season we found that HbAS, but not HbAC, significantly reduced the risk of malaria compared to HbAA. IgG levels to MSP1 and MSP2 at the start of this transmission season inversely correlated with malaria incidence after adjusting for age and Hb type. However, HbAS children had significantly lower IgG levels to EBA175 and MSP2 compared to HbAA children. On the other hand, HbAC children had similar IgG levels to all four antigens. The parasite growth-inhibitory activity of purified IgG samples did not differ significantly by Hb type. Changes in antigen-specific IgG levels during the 2009 transmission and 2010 dry seasons also did not differ by Hb type, and none of these IgG levels dropped significantly during the dry season. These data suggest that sickle-cell trait does not reduce the risk of malaria by enhancing the acquisition of IgG responses to merozoite antigens

High <i>Plasmodium falciparum</i> longitudinal prevalence is associated with high multiclonality and reduced clinical malaria risk in a seasonal transmission area of Mali

<div><p>The effects of persistent <i>Plasmodium falciparum</i> (Pf) infection and multiclonality on subsequent risk of clinical malaria have been reported, but the relationship between these 2 parameters and their relative impacts on the clinical outcome of infection are not understood. A longitudinal cohort study was conducted in a seasonal and high-transmission area of Mali, in which 500 subjects aged 1–65 years were followed for 1 year. Blood samples were collected every 2 weeks, and incident malaria cases were diagnosed and treated. Pf infection in each individual at each time point was assessed by species-specific nested-PCR, and Pf longitudinal prevalence per person (PfLP, proportion of Pf-positive samples over 1 year) was calculated. Multiclonality of Pf infection was measured using a 24-SNP DNA barcoding assay at 4 time-points (two in wet season, and two in dry season) over one year. PfLP was positively correlated with multiclonality at each time point (all r≥0.36; all <i>P</i>≤0.011). When host factors (e.g., age, gender), PfLP, and multiclonality (at the beginning of the transmission season) were analyzed together, only increasing age and high PfLP were associated with reduced clinical malaria occurrence or reduced number of malaria episodes (for both outcomes, <i>P</i><0.001 for age, and <i>P</i> = 0.005 for PfLP). When age, PfLP and baseline Pf positivity were analyzed together, the effect of high PfLP remained significant even after adjusting for the other two factors (<i>P</i> = 0.001 for malaria occurrence and <i>P</i><0.001 for number of episodes). In addition to host age and baseline Pf positivity, both of which have been reported as important modifiers of clinical malaria risk, our results demonstrate that persistent parasite carriage, but not baseline multiclonality, is associated with reduced risk of clinical disease in this population. Our study emphasizes the importance of considering repeated parasite exposure in future studies that evaluate clinical malaria risk.</p></div

Increases in merozoite antigen-specific IgG levels during a transmission season do not differ by Hb type.

<p>For each child, the change in IgG level from May to December 2009 was calculated for each antigen (A, AMA1-3D7; B, MSP1-3D7; C, EBA175-3D7; D, MSP2-3D7). All responses below the limit of detection (44 ELISA units) were assigned a value of 22 ELISA units. Median and interquartile range are shown. Positive values represent increases in IgG levels at the end of the transmission season. Changes in IgG levels were not significantly different among the three Hb types for any antigen (p>0.05 by Kruskal-Wallis tests).</p

Results of multivariate regression analysis of clinical malaria risk, including baseline Pf positivity^a.

<p>Results of multivariate regression analysis of clinical malaria risk, including baseline Pf positivity<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170948#t004fn001" target="_blank">^a</a>.</p

Multiclonality of <i>P</i>. <i>falciparum</i> infection at 4 time-points.

<p>(A) Distribution of complexity of infection (COI) values estimated by COIL. The proportions of individuals with COI = 1 (white), COI = 2 (light gray), and COI≥3 (dark gray) at each time-point are indicated. (B) Distribution of polymorphic proportion (PmP) values calculated from polymorphic genotypes in the 24-SNP DNA barcode. Box-and-whisker plots show median, interquartile range (IQR), and 1.5x IQR. There were no significant differences in the COI and PmP distributions among the 4 time-points as determined by Chi-squared and Kruskal-Wallis tests, respectively.</p

Cross-sectional prevalence of <i>P</i>. <i>falciparum</i> (Pf) infection and 2-week incidence of clinical malaria from June 2013 to May 2014.

<p>Left y-axis: Pf prevalence measured by nested-PCR; dark gray bars represent Pf prevalence. Right y-axis: number of clinical malaria cases recorded during each 2-week period preceding a blood sampling visit; light gray bars represent 2-week incidence. The time of visit is indicated on the x-axis, with V1 and V2 indicating the first and second blood sampling visits, respectively, for the months indicated.</p

Correlation between polymorphic proportion (PmP) and <i>P</i>. <i>falciparum</i> longitudinal prevalence (PfLP).

<p>PmP positively correlates with PfLP at all 4 time-points: (A) Jun-V1 (r = 0.47, 95% confidence interval = 0.30–0.61, <i>P</i><0.001, Spearman rank correlation test); (B) Nov-V1 (r = 0.36, 0.18–0.52, <i>P</i><0.001); (C) Feb-V1 (r = 0.42, 0.15–0.63, <i>P</i> = 0.003); and (D) Apr-V1 (r = 0.39, 0.09–0.63, <i>P</i> = 0.011)</p