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Antimicrobial Agents and Chemotherapy Mar 2018Treatment recommendations for and malaria are largely based on anecdotal evidence. The aim of this prospective study, conducted in Gabon, was to systematically assess...
Prospective Clinical Trial Assessing Species-Specific Efficacy of Artemether-Lumefantrine for the Treatment of Plasmodium malariae, Plasmodium ovale, and Mixed Plasmodium Malaria in Gabon.
Treatment recommendations for and malaria are largely based on anecdotal evidence. The aim of this prospective study, conducted in Gabon, was to systematically assess the efficacy and safety of artemether-lumefantrine for the treatment of patients with uncomplicated or species monoinfections or mixed infections. Patients with microscopically confirmed , , or mixed-species malaria with at least one of these two species were treated with an oral, fixed-dose combination of artemether-lumefantrine for 3 consecutive days. The primary endpoints were per-protocol PCR-corrected adequate clinical and parasitological response (ACPR) on days 28 and 42. Tolerability and safety were recorded throughout the follow-up period. Seventy-two participants (42 male and 30 female) were enrolled; 62.5% of them had PCR-corrected mixed infections. Per protocol, PCR-corrected ACPR rates were 96.6% (95% confidence interval [CI], 91.9 to 100) on day 28 and 94.2% (95% CI, 87.7 to 100) on day 42. Considering species independently from their coinfecting species, day 42 ACPR rates were 95.5% (95% CI, 89.0 to 100) for , 100% (exact CI, 84.6 to 100) for , 100% (exact CI, 76.8 to 100) for , and 90.9% (95% CI, 70.7 to 100) for Study drug-related adverse events were generally mild or moderate. In conclusion, this clinical trial demonstrated satisfying antimalarial activity of artemether-lumefantrine against , , , and mixed infections, with per-protocol efficacies of 90% to 100% and without evident tolerability or safety concerns. (This trial was registered in the clinical study database ClinicalTrials.gov under the identifier NCT02528279.).
Topics: Adolescent; Adult; Antimalarials; Artemether; Child; Child, Preschool; Female; Gabon; Humans; Lumefantrine; Male; Plasmodium malariae; Plasmodium ovale; Young Adult
PubMed: 29311086
DOI: 10.1128/AAC.01758-17 -
The Journal of Infectious Diseases Mar 2020Plasmodium malariae is considered a minor malaria parasite, although its global disease burden is underappreciated. The aim of this study was to develop an induced...
BACKGROUND
Plasmodium malariae is considered a minor malaria parasite, although its global disease burden is underappreciated. The aim of this study was to develop an induced blood-stage malaria (IBSM) model of P. malariae to study parasite biology, diagnostic assays, and treatment.
METHODS
This clinical trial involved 2 healthy subjects who were intravenously inoculated with cryopreserved P. malariae-infected erythrocytes. Subjects were treated with artemether-lumefantrine after development of clinical symptoms. Prior to antimalarial therapy, mosquito-feeding assays were performed to investigate transmission, and blood samples were collected for rapid diagnostic testing and parasite transcription profiling. Serial blood samples were collected for biomarker analysis.
RESULTS
Both subjects experienced symptoms and signs typical of early malaria. Parasitemia was detected 7 days after inoculation, and parasite concentrations increased until antimalarial treatment was initiated 25 and 21 days after inoculation for subjects 1 and 2 respectively (peak parasitemia levels, 174 182 and 50 291 parasites/mL, respectively). The parasite clearance half-life following artemether-lumefantrine treatment was 6.7 hours. Mosquito transmission was observed for 1 subject, while in vivo parasite transcription and biomarkers were successfully profiled.
CONCLUSIONS
An IBSM model of P. malariae has been successfully developed and may be used to study the biology of, diagnostic testing for, and treatment of this neglected malaria species.
CLINICAL TRIALS REGISTRATION
ACTRN12617000048381.
Topics: Adolescent; Animals; Anopheles; Antimalarials; Artemether, Lumefantrine Drug Combination; Feeding Behavior; Humans; Malaria; Male; Parasitemia; Plasmodium malariae; Transcriptome; Young Adult
PubMed: 30852586
DOI: 10.1093/infdis/jiz102 -
Malaria Journal Aug 2020Plasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. Studies on genetic polymorphisms of anti-malarial drug...
BACKGROUND
Plasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. Studies on genetic polymorphisms of anti-malarial drug target genes in P. malariae are limited. Previous reports have shown polymorphisms in the P. malariae dihydrofolate reductase gene associated with pyrimethamine resistance and linked to pyrimethamine drug pressure. This study investigated polymorphisms of the P. malariae homologous genes, chloroquine resistant transporter and multidrug resistant 1, associated with chloroquine and mefloquine resistance in Plasmodium falciparum.
METHODS
The orthologous P. malariae crt and mdr1 genes were studied in 95 patients with P. malariae infection between 2002 and 2016 from Thailand (N = 51) and Myanmar (N = 44). Gene sequences were analysed using BioEdit, MEGA7, and DnaSP programs. Mutations and gene amplifications were compared with P. falciparum and Plasmodium vivax orthologous genes. Protein topology models derived from the observed pmcrt and pmmdr1 haplotypes were constructed and analysed using Phyre2, SWISS MODEL and Discovery Studio Visualization V 17.2.
RESULTS
Two non-synonymous mutations were observed in exon 2 (H53P, 40%) and exon 8 (E278D, 44%) of pmcrt. The topology model indicated that H53P and E278D were located outside of the transmembrane domain and were unlikely to affect protein function. Pmmdr1 was more diverse than pmcrt, with 10 non-synonymous and 3 synonymous mutations observed. Non-synonymous mutations were located in the parasite cytoplasmic site, transmembrane 11 and nucleotide binding domains 1 and 2. Polymorphisms conferring amino acid changes in the transmembrane and nucleotide binding domains were predicted to have some effect on PmMDR1 conformation, but were unlikely to affect protein function. All P. malariae parasites in this study contained a single copy of the mdr1 gene.
CONCLUSIONS
The observed polymorphisms in pmcrt and pmmdr1 genes are unlikely to affect protein function and unlikely related to chloroquine drug pressure. Similarly, the absence of pmmdr1 copy number variation suggests limited mefloquine drug pressure on the P. malariae parasite population, despite its long time use in Thailand for the treatment of falciparum malaria.
Topics: Chloroquine; Drug Resistance; Insecticides; Mefloquine; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins; Myanmar; Plasmodium malariae; Polymorphism, Genetic; Protozoan Proteins; Thailand
PubMed: 32867773
DOI: 10.1186/s12936-020-03391-6 -
Malaria Journal Jan 2020Molecular genotyping in Plasmodium serves many aims including providing tools for studying parasite population genetics and distinguishing recrudescence from...
BACKGROUND
Molecular genotyping in Plasmodium serves many aims including providing tools for studying parasite population genetics and distinguishing recrudescence from reinfection. Microsatellite typing, insertion-deletion (INDEL) and single nucleotide polymorphisms is used for genotyping, but only limited information is available for Plasmodium malariae, an important human malaria species. This study aimed to provide a set of genetic markers to facilitate the study of P. malariae population genetics.
METHODS
Markers for microsatellite genotyping and pmmsp1 gene polymorphisms were developed and validated in symptomatic P. malariae field isolates from Myanmar (N = 37). Fragment analysis was used to determine allele sizes at each locus to calculate multiplicity of infections (MOI), linkage disequilibrium, heterozygosity and construct dendrograms. Nucleotide diversity (π), number of haplotypes, and genetic diversity (H) were assessed and a phylogenetic tree was constructed. Genome-wide microsatellite maps with annotated regions of newly identified markers were constructed.
RESULTS
Six microsatellite markers were developed and tested in 37 P. malariae isolates which showed sufficient heterozygosity (0.530-0.922), and absence of linkage disequilibrium (I=0.03, p value > 0.05) (N = 37). In addition, a tandem repeat (VNTR)-based pmmsp1 INDEL polymorphisms marker was developed and assessed in 27 P. malariae isolates showing a nucleotide diversity of 0.0976, haplotype gene diversity of 0.698 and identified 14 unique variants. The size of VNTR consensus repeat unit adopted as allele was 27 base pairs. The markers Pm12_426 and pmmsp1 showed greatest diversity with heterozygosity scores of 0.920 and 0.835, respectively. Using six microsatellites markers, the likelihood that any two parasite strains would have the same microsatellite genotypes was 8.46 × 10 and was further reduced to 1.66 × 10 when pmmsp1 polymorphisms were included.
CONCLUSIONS
Six novel microsatellites genotyping markers and a set of pmmsp1 VNTR-based INDEL polymorphisms markers for P. malariae were developed and validated. Each marker could be independently or in combination employed to access genotyping of the parasite. The newly developed markers may serve as a useful tool for investigating parasite diversity, population genetics, molecular epidemiology and for distinguishing recrudescence from reinfection in drug efficacy studies.
Topics: Gene Frequency; Genetic Markers; Genetic Variation; Genotyping Techniques; Linkage Disequilibrium; Merozoite Surface Protein 1; Microsatellite Repeats; Plasmodium malariae; Polymerase Chain Reaction; Polymorphism, Genetic; Reproducibility of Results
PubMed: 31992308
DOI: 10.1186/s12936-020-3122-2 -
EBioMedicine Sep 2015
Topics: Animals; Haplorhini; Host-Parasite Interactions; Humans; Malaria; Monkey Diseases; Plasmodium malariae; Zoonoses
PubMed: 26501096
DOI: 10.1016/j.ebiom.2015.08.035 -
PloS One 2017One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium...
One hundred and fifty-two blood samples of non-human primates of thirteen rescue centers in Costa Rica were analyzed to determine the presence of species of Plasmodium using thick blood smears, semi-nested multiplex polymerase chain reaction (SnM-PCR) for species differentiation, cloning and sequencing for confirmation. Using thick blood smears, two samples were determined to contain the Plasmodium malariae parasite, with SnM-PCR, a total of five (3.3%) samples were positive to P. malariae, cloning and sequencing confirmed both smear samples as P. malariae. One sample amplified a larger and conserved region of 18S rDNA for the genus Plasmodium and sequencing confirmed the results obtained microscopically and through SnM-PCR tests. Sequencing and construction of a phylogenetic tree of this sample revealed that the P. malariae/P. brasilianum parasite (GenBank KU999995) found in a howler monkey (Alouatta palliata) is identical to that recently reported in humans in Costa Rica. The SnM-PCR detected P. malariae/P. brasilianum parasite in different non-human primate species in captivity and in various regions of the southern Atlantic and Pacific coast of Costa Rica. The similarity of the sequences of parasites found in humans and a monkey suggests that monkeys may be acting as reservoirs of P.malariae/P. brasilianum, for which reason it is important, to include them in control and eradication programs.
Topics: Animals; Costa Rica; DNA, Protozoan; Disease Reservoirs; Epidemiological Monitoring; Female; Haplorhini; Humans; Malaria; Male; Monkey Diseases; Phylogeny; Plasmodium; Plasmodium malariae; RNA, Ribosomal, 18S
PubMed: 28125696
DOI: 10.1371/journal.pone.0170704 -
Malaria Journal Jul 2016In an effort to improve surveillance for epidemiological and clinical outcomes, rapid diagnostic tests (RDTs) have become increasingly widespread as cost-effective and...
Low prevalence of Plasmodium malariae and Plasmodium ovale mono-infections among children in the Democratic Republic of the Congo: a population-based, cross-sectional study.
BACKGROUND
In an effort to improve surveillance for epidemiological and clinical outcomes, rapid diagnostic tests (RDTs) have become increasingly widespread as cost-effective and field-ready methods of malaria diagnosis. However, there are concerns that using RDTs specific to Plasmodium falciparum may lead to missed detection of other malaria species such as Plasmodium malariae and Plasmodium ovale.
METHODS
Four hundred and sixty six samples were selected from children under 5 years old in the Democratic Republic of the Congo (DRC) who took part in a Demographic and Health Survey (DHS) in 2013-14. These samples were first tested for all Plasmodium species using an 18S ribosomal RNA-targeted real-time PCR; malaria-positive samples were then tested for P. falciparum, P. malariae and P. ovale using a highly sensitive nested PCR.
RESULTS
The prevalence of P. falciparum, P. malariae and P. ovale were 46.6, 12.9 and 8.3 %, respectively. Most P. malariae and P. ovale infections were co-infected with P. falciparum-the prevalence of mono-infections of these species were only 1.0 and 0.6 %, respectively. Six out of these eight mono-infections were negative by RDT. The prevalence of P. falciparum by the more sensitive nested PCR was higher than that found previously by real-time PCR.
CONCLUSIONS
Plasmodium malariae and P. ovale remain endemic at a low rate in the DRC, but the risk of missing malarial infections of these species due to falciparum-specific RDT use is low. The observed prevalence of P. falciparum is higher with a more sensitive PCR method.
Topics: Adult; Child, Preschool; Cross-Sectional Studies; Democratic Republic of the Congo; Female; Humans; Infant; Infant, Newborn; Malaria; Male; Plasmodium malariae; Plasmodium ovale; Polymerase Chain Reaction; Prevalence; RNA, Protozoan; RNA, Ribosomal, 18S; Real-Time Polymerase Chain Reaction
PubMed: 27392905
DOI: 10.1186/s12936-016-1409-0 -
Revista Do Instituto de Medicina... 2020Malaria is an infectious vector-borne disease with other important routes of transmission, such as blood transfusion and organ/tissue transplantation, due to...
Malaria is an infectious vector-borne disease with other important routes of transmission, such as blood transfusion and organ/tissue transplantation, due to asymptomatic reservoirs of Plasmodium presenting with low parasitemia. Reports of transfusion-transmitted malaria have shown that in immunosuppressed recipients, infections can be fatal if they are not diagnosed and timely treated. All Plasmodium species can survive on blood components at temperatures from 2 to 6 °C for some days or even weeks. This report describes two candidates for blood donation harboring Plasmodium, infected in an area considered non-endemic. Blood samples were collected from donors who attended a blood bank in Sao Paulo and tested by microscopy, qPCR for Plasmodium genus-specific amplification, targeting the parasite 18S ribosomal subunit gene and a multiplex qPCR based on mtDNA of the five species. Under microscopy, only structures resembling Plasmodium were observed. The qPCR whose standard curve tested parasites varying from 2 to 0.1 parasites/ µL, showed the presence of Plasmodium DNA in the two blood donors, as did the multiplex qPCR that revealed the presence of P. malariae. The prevalence of positive donors varies according to the level of transmission, ranging from 0.7 to 55% in endemic areas. In non-endemic regions, prevalences are lower, however, transfusion malaria can evolve to severe cases, due to the lack of suspicion of this transmission route. Asymptomatic donors from low transmission regions pose a risk to blood banks, with particular emphasis on those located in areas with malaria elimination goals.
Topics: Adult; Antibodies, Protozoan; Blood Donors; Female; Humans; Malaria; Male; Multiplex Polymerase Chain Reaction; Parasitemia; Plasmodium malariae
PubMed: 33331519
DOI: 10.1590/S1678-9946202062100 -
Emerging Infectious Diseases Aug 2017Plasmodium malariae is the only human malaria parasite species with a 72-hour intraerythrocytic cycle and the ability to persist in the host for life. We present a case...
Plasmodium malariae is the only human malaria parasite species with a 72-hour intraerythrocytic cycle and the ability to persist in the host for life. We present a case of a P. malariae infection with clinical recrudescence after directly observed administration of artemether/lumefantrine. By using whole-genome sequencing, we show that the initial infection was polyclonal and the recrudescent isolate was a single clone present at low density in the initial infection. Haplotypic analysis of the clones in the initial infection revealed that they were all closely related and were presumably recombinant progeny originating from the same infective mosquito bite. We review possible explanations for the P. malariae treatment failure and conclude that a 3-day artemether/lumefantrine regimen is suboptimal for this species because of its long asexual life cycle.
Topics: Adult; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Drug Resistance; Ethanolamines; Fluorenes; Humans; Hydroxychloroquine; Malaria; Male; Plasmodium malariae; Primaquine; Recurrence
PubMed: 28430103
DOI: 10.3201/eid2308.161582 -
Malaria Journal Oct 2021Plasmodium falciparum is responsible for the vast majority of (severe) clinical malaria cases in most African settings. Other Plasmodium species often go undiagnosed but...
BACKGROUND
Plasmodium falciparum is responsible for the vast majority of (severe) clinical malaria cases in most African settings. Other Plasmodium species often go undiagnosed but may still have clinical consequences.
CASE PRESENTATION
Here, five cases of Plasmodium malariae infections from Eastern Uganda (aged 2-39 years) are presented. These infections were all initially mistaken for P. falciparum, but Plasmodium schizonts (up to 2080/µL) were identified by microscopy. Clinical signs included history of fever and mild anaemia.
CONCLUSION
These findings highlight the importance of considering non-falciparum species as the cause of clinical malaria. In areas of intense P. falciparum transmission, where rapid diagnostic tests that detect only P. falciparum antigens are commonly used, non-falciparum malaria cases may be missed.
Topics: Adolescent; Adult; Female; Fever; Humans; Infant; Malaria; Malaria, Falciparum; Male; Plasmodium falciparum; Plasmodium malariae; Uganda; Young Adult
PubMed: 34715876
DOI: 10.1186/s12936-021-03962-1