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Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses.

ABSTRACT: BACKGROUND:In malaria endemic populations, complex patterns of Plasmodium vivax and Plasmodium falciparum blood-stage infection dynamics may be observed. Genotyping samples from longitudinal cohort studies for merozoite surface protein (msp) variants increases the information available in the data, allowing multiple infecting parasite clones in a single individual to be identified. msp genotyped samples from two longitudinal cohorts in Papua New Guinea (PNG) and Thailand were analysed using a statistical model where the times of acquisition and clearance of each clone in every individual were estimated using a process of data augmentation. RESULTS:For the populations analysed, the duration of blood-stage P. falciparum infection was estimated as 36 (95% Credible Interval (CrI): 29, 44) days in PNG, and 135 (95% CrI 94, 191) days in Thailand. Experiments on simulated data indicated that it was not possible to accurately estimate the duration of blood-stage P. vivax infections due to the lack of identifiability between a single blood-stage infection and multiple, sequential blood-stage infections caused by relapses. Despite this limitation, the method and data point towards short duration of blood-stage P. vivax infection with a lower bound of 24 days in PNG, and 29 days in Thailand. On an individual level, P. vivax recurrences cannot be definitively classified into re-infections, recrudescences or relapses, but a probabilistic relapse phenotype can be assigned to each P. vivax sample, allowing investigation of the association between epidemiological covariates and the incidence of relapses. CONCLUSION:The statistical model developed here provides a useful new tool for in-depth analysis of malaria data from longitudinal cohort studies, and future application to data sets with multi-locus genotyping will allow more detailed investigation of infection dynamics.

SUBMITTER: White MT

PROVIDER: S-EPMC5905131 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses.

White Michael T MT Karl Stephan S Koepfli Cristian C Longley Rhea J RJ Hofmann Natalie E NE Wampfler Rahel R Felger Ingrid I Smith Tom T Nguitragool Wang W Sattabongkot Jetsumon J Robinson Leanne L Ghani Azra A Mueller Ivo I

Malaria journal 20180417 1

<h4>Background</h4>In malaria endemic populations, complex patterns of Plasmodium vivax and Plasmodium falciparum blood-stage infection dynamics may be observed. Genotyping samples from longitudinal cohort studies for merozoite surface protein (msp) variants increases the information available in the data, allowing multiple infecting parasite clones in a single individual to be identified. msp genotyped samples from two longitudinal cohorts in Papua New Guinea (PNG) and Thailand were analysed us ...[more]

PMID: 29665803

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Project description:BACKGROUND:Adding 8-aminoquinoline to the treatment of falciparum, in addition to vivax malaria, in locations where infections with both species are prevalent could prevent vivax reactivation. The potential risk of haemolysis under a universal radical cure policy using 8-aminoquinoline needs to be weighed against the benefit of preventing repeated vivax episodes. Estimating the frequency of sequential Plasmodium vivax infections following either falciparum or vivax malaria episodes is needed for such an assessment. METHODS:Quarterly surveillance data collected during a mass drug administration trial in the Greater Mekong Subregion in 2013-17 was used to estimate the probability of asymptomatic sequential infections by the same and different Plasmodium species. Asymptomatic Plasmodium infections were detected by high-volume ultrasensitive qPCR. Quarterly surveys of asymptomatic Plasmodium prevalence were used to estimate the probability of a P. vivax infection following Plasmodium falciparum and P. vivax infections. RESULTS:16,959 valid sequential paired test results were available for analysis. Of these, 534 (3%) had an initial P. falciparum monoinfection, 1169 (7%) a P. vivax monoinfection, 217 (1%) had mixed (P. falciparum + P. vivax) infections, and 15,039 (89%) had no Plasmodium detected in the initial survey. Participants who had no evidence of a Plasmodium infection had a 4% probability to be found infected with P. vivax during the subsequent survey. Following an asymptomatic P. falciparum monoinfection participants had a 9% probability of having a subsequent P. vivax infection (RR 2.4; 95% CI 1.8 to 3.2). Following an asymptomatic P. vivax monoinfection, the participants had a 45% probability of having a subsequent P. vivax infection. The radical cure of 12 asymptomatic P. falciparum monoinfections would have prevented one subsequent P. vivax infection, whereas treatment of 2 P. vivax monoinfections may suffice to prevent one P. vivax relapse. CONCLUSION:Universal radical cure could play a role in the elimination of vivax malaria. The decision whether to implement universal radical cure for P. falciparum as well as for P. vivax depends on the prevalence of P. falciparum and P. vivax infections, the prevalence and severity of G6PD deficiency in the population and the feasibility to administer 8-aminoquinoline regimens safely. Trial registration ClinicalTrials.gov Identifier: NCT01872702, first posted June 7th 2013, https://clinicaltrials.gov/ct2/show/NCT01872702. This study was registered with ClinicalTrials.gov under NCT02802813 on 16th June 2016. https://clinicaltrials.gov/ct2/show/NCT02802813.

Project description:BACKGROUND:Parasite genetic diversity and multiplicity of infection (MOI) affect clinical outcomes, response to drug treatment and naturally-acquired or vaccine-induced immunity. Traditional methods often underestimate the frequency and diversity of multiclonal infections due to technical sensitivity and specificity. Next-generation sequencing techniques provide a novel opportunity to study complexity of parasite populations and molecular epidemiology. METHODS:Symptomatic and asymptomatic Plasmodium vivax samples were collected from health centres/hospitals and schools, respectively, from 2011 to 2015 in Ethiopia. Similarly, both symptomatic and asymptomatic Plasmodium falciparum samples were collected, respectively, from hospitals and schools in 2005 and 2015 in Kenya. Finger-pricked blood samples were collected and dried on filter paper. Long amplicon (> 400 bp) deep sequencing of merozoite surface protein 1 (msp1) gene was conducted to determine multiplicity and molecular epidemiology of P. vivax and P. falciparum infections. The results were compared with those based on short amplicon (117 bp) deep sequencing. RESULTS:A total of 139 P. vivax and 222 P. falciparum samples were pyro-sequenced for pvmsp1 and pfmsp1, yielding a total of 21 P. vivax and 99 P. falciparum predominant haplotypes. The average MOI for P. vivax and P. falciparum were 2.16 and 2.68, respectively, which were significantly higher than that of microsatellite markers and short amplicon (117 bp) deep sequencing. Multiclonal infections were detected in 62.2% of the samples for P. vivax and 74.8% of the samples for P. falciparum. Four out of the five subjects with recurrent P. vivax malaria were found to be a relapse 44-65 days after clearance of parasites. No difference was observed in MOI among P. vivax patients of different symptoms, ages and genders. Similar patterns were also observed in P. falciparum except for one study site in Kenyan lowland areas with significantly higher MOI. CONCLUSIONS:The study used a novel method to evaluate Plasmodium MOI and molecular epidemiological patterns by long amplicon ultra-deep sequencing. The complexity of infections were similar among age groups, symptoms, genders, transmission settings (spatial heterogeneity), as well as over years (pre- vs. post-scale-up interventions). This study demonstrated that long amplicon deep sequencing is a useful tool to investigate multiplicity and molecular epidemiology of Plasmodium parasite infections.

Project description:BACKGROUND: With 75% of the Ethiopian population at risk of malaria, accurate diagnosis is crucial for malaria treatment in endemic areas where Plasmodium falciparum and Plasmodium vivax co-exist. The present study evaluated the performance of regular microscopy in accurate identification of Plasmodium spp. in febrile patients visiting health facilities in southern Ethiopia. METHODS: A cross-sectional study design was employed to recruit study subjects who were microscopically positive for malaria parasites and attending health facilities in southern Ethiopia between August and December 2011. Of the 1,416 febrile patients attending primary health facilities, 314 febrile patients, whose slides were positive for P. falciparum, P. vivax or mixed infections using microscopy, were re-evaluated for their infection status by PCR. Finger-prick blood samples were used for parasite genomic DNA extraction. Phylogenetic analyses were performed to reconstruct the distribution of different Plasmodium spp. across the three geographical areas. RESULTS: Of the 314 patients with a positive thick blood smear, seven patients (2%) were negative for any of the Plasmodium spp. by nested PCR. Among 180 microscopically diagnosed P. falciparum cases, 111 (61.7%) were confirmed by PCR, 44 (24.4%) were confirmed as P. vivax, 18 (10%) had mixed infections with P. falciparum and P. vivax and two (1.1%) were mixed infections with P. falciparum and P. malariae and five (2.8%) were negative for any of the Plasmodium spp. Of 131 microscopically diagnosed P. vivax cases, 110 (84%) were confirmed as P. vivax, 14 (10.7%) were confirmed as P. falciparum, two (1.5%) were P. malariae, three (2.3%) with mixed infections with P. falciparum and P. vivax and two (1.5%) were negative for any of the Plasmodium spp. Plasmodium falciparum and P. vivax mixed infections were observed. Plasmodium malariae was detected as mono and mixed infections in four individuals. CONCLUSION: False positivity, under-reporting of mixed infections and a significant number of species mismatch needs attention and should be improved for appropriate diagnosis. The detection of substantial number of false positive results by molecular methodologies may provide the accurate incidence of circulating Plasmodium species in the geographical region and has important repercussions in understanding malaria epidemiology and subsequent control.

Project description:Malaria transmission in Latin America is generally hypoendemic and unstable, with Plasmodium vivax as the most prevalent species. However, only a few studies have been carried out in areas with low and unstable transmission, whereas the clinical profile of malaria has been broadly described in hyperendemic areas. The pattern of clinical manifestations and laboratory findings in low to moderate endemic areas of Colombia is reported here.A passive surveillance study was conducted between 2011 and 2013 involving 1,328 patients with Plasmodium falciparum, P. vivax or mixed malaria infections attending malaria points-of-care of four malaria endemic-areas with distinct transmission intensities and parasite distribution. Trained physicians recorded clinical symptoms and signs as well as socio-demographic characteristics of study participants. Haematological, biochemical and urine tests were performed at the time of diagnosis.Out of 1,328 cases, 673 (50.7%) were caused by P. vivax; 650 (48.9%) were due to P. falciparum; and five (0.4%) patients had mixed infections (P. falciparum/P. vivax). Most patients (92.5%) presented with uncomplicated malaria characterized by fever, chills, headache, sweating, myalgia/arthralgia and parasitaemia ≤ 20,000 parasites/μL. Fever, tachycardia, pallor and abdominal pain on palpation were more frequent in P. falciparum patients, whereas mild hepatomegaly and splenomegaly were mostly observed with P. vivax. Non-severe anaemia (Hb 7.0-10.9 g/dL) was observed in 20% of the subjects, whereas severe anaemia (Hb < 7.0 g/dL) was present in four patients. Half of the patients presented thrombocytopaenia regardless of parasite species. Leukopaenia, neutrophilia and monocytosis were frequently observed in patients infected with P. falciparum. Mild-to-moderate biochemical alterations were present in ~25% of the patients, particularly abnormal bilirubin in those with P. falciparum and abnormal transaminases in P. vivax malaria patients. Proteinuria was present in ~50% of the patients regardless of parasite species, whereas haemoglobinuria was more common in P. vivax infections. Only 7.5% of the cases were classified as clinically severe malaria, caused by both P. vivax and P. falciparum.The high prevalence of uncomplicated malaria associated with moderate parasitaemia suggests the importance of timely diagnosis and effective treatment and encourages new activities to further decrease complicated malaria cases and mortality.

Dataset Information

Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses.

Publications

Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses.

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