Dataset Information

Plasma Plasmodium falciparum Histidine-rich Protein 2 Concentrations in Children With Malaria Infections of Differing Severity in Kilifi, Kenya.

ABSTRACT:

Background

Most previous studies support a direct link between total parasite load and the clinical severity of Plasmodium falciparum malaria infections.

Methods

We estimated P. falciparum parasite loads in 3 groups of children with malaria infections of differing severity: (1) children with World Health Organization-defined severe malaria (n = 1544), (2) children admitted with malaria but without features of severity (n = 200), and (3) children in the community with asymptomatic parasitemia (n = 33).

Results

Peripheral parasitemias were highest in those with uncomplicated malaria (geometric mean [GM] parasite count, 111 064/μL; 95% confidence interval, CI, 86 798-141 819/μL), almost 3 times higher than in those with severe malaria (39 588/μL; 34 990-44 791/μL) and >100 times higher than in those with asymptomatic malaria (1092/μL; 523-2280/μL). However, the GM P. falciparum histidine-rich protein 2 (PfHRP2) values (95% CI) increased with severity, being 7 (4-12) ng/mL in asymptomatic malaria, 843 (655-1084) ng/mL in uncomplicated malaria, and 1369 (1244-1506) ng/mL in severe malaria. PfHRP2 concentrations were markedly lower in the subgroup of patients with severe malaria and concomitant invasive bacterial infections of blood or cerebrospinal fluid (GM concentration, 312 ng/mL; 95% CI, 175-557 ng/mL; P < .001) than in those without such infections (1439 ng/mL; 1307-1584; P < .001).

Conclusions

The clinical severity of malaria infections related strongly to the total burden of P. falciparum parasites. A quantitative test for plasma concentrations of PfHRP2 could be useful in identifying children at the greatest clinical risk and identifying critically ill children in whom malaria is not the primary cause.

SUBMITTER: Uyoga S

PROVIDER: S-EPMC8492128 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Knowledge of how malaria infections spread locally is important both for the design of targeted interventions aiming to interrupt malaria transmission and the design of trials to assess the interventions. A previous analysis of 1602 genotyped Plasmodium falciparum parasites in Kilifi, Kenya collected over 12 years found an interaction between time and geographic distance: the mean number of single nucleotide polymorphism (SNP) differences was lower for pairs of infections which were both a shorter time interval and shorter geographic distance apart. We determine whether the empiric pattern could be reproduced by a simple model, and what mean geographic distances between parent and offspring infections and hypotheses about genotype-specific immunity or a limit on the number of infections would be consistent with the data. We developed an individual-based stochastic simulation model of households, people and infections. We parameterized the model for the total number of infections, and population and household density observed in Kilifi. The acquisition of new infections, mutation, recombination, geographic location and clearance were included. We fit the model to the observed numbers of SNP differences between pairs of parasite genotypes. The patterns observed in the empiric data could be reproduced. Although we cannot rule out genotype-specific immunity or a limit on the number of infections per individual, they are not necessary to account for the observed patterns. The mean geographic distance between parent and offspring malaria infections for the base model was 0.5?km (95% CI 0.3-1.5), for a distribution with 68% of distances shorter than the mean. Very short mean distances did not fit well, but mixtures of distributions were also consistent with the data. For a pathogen which undergoes meiosis in a setting with moderate transmission and a low coverage of infections, analytic methods are limited but an individual-based model can be used with genotyping data to estimate parameter values and investigate hypotheses about underlying processes.

Project description:BackgroundMalaria rapid diagnostic tests (RDTs) are precious tools to diagnose malaria. Most RDTs used currently are based on the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) in a patient's blood. However, concern has been raised in recent years that deletion of pfhrp2 in the parasite could affect the accuracy of PfHRP2-based RDTs. In addition, genetic variation in pfhrp2 might influence the accuracy and sensitivity of RDTs. In this study, the genetic variation in pfhrp2 and pfhrp3 in Myanmar P. falciparum isolates was analysed.MethodsBlood samples were collected from malaria patients who were infected with P. falciparum in Mandalay, Naung Cho, Tha Beik Kyin, and Pyin Oo Lwin, Upper Myanmar between 2013 and 2015. The pfhrp2 and pfhrp3 were amplified by nested polymerase chain reaction (PCR), cloned and sequenced. Genetic variation in Myanmar pfhrp2 and pfhrp3 was analysed using the DNASTAR program. Comparative analysis of Myanmar and global pfhrp2 and pfhrp3 isolates was also performed.ResultsOne-hundred and two pfhrp2 and 89 pfhrp3 were amplified from 105 blood samples, of which 84 pfhrp2 and 56 pfhrp3 sequences were obtained successfully. Myanmar pfhrp2 and pfhrp3 showed high levels of genetic variation with different arrangements of distinct repeat types, which further classified Myanmar pfhrp2 and pfhrp3 into 76 and 47 haplotypes, respectively. Novel amino acid changes were also found in Myanmar pfhrp2 and pfhrp3, but their frequencies were very low. Similar structural organization was shared by Myanmar and global pfhrp2 and pfhrp3, and differences in frequencies of repeat types and lengths were also observed between and among global isolates.ConclusionLength polymorphisms and amino acid substitutions generated extensive genetic variation in Myanmar pfhrp2 and pfhrp3. Comparative analysis revealed that global pfhrp2 and pfhrp3 share similar structural features, as well as extensive length polymorphisms and distinct organizations of repeat types. These results provide a better understanding of the genetic structure of pfhrp2 and pfhrp3 in global P. falciparum populations and suggest useful information to develop RDTs with improved quality.