In recent years Venezuela has faced a severe economic crisis precipitated by political instability and a significant reduction in oil revenue. Public health provision has suffered particularly. Long-term shortages of medicines and medical supplies and an exodus of trained personnel have occurred against the backdrop of a surge in vector-borne parasitic and arboviral infections. Herein, we aim to assess comprehensively the impact of Venezuela's healthcare crisis on vectorborne diseases and the spillover to neighbouring countries. Methods Alongside the ongoing challenges affecting the healthcare system, health-indicator statistics have become increasingly scarce. Official data from the Ministry of Health, for example, are no longer available. To provide and update on vector-borne disease in Venezuela, this study used individualized data from nongovernmental organizations, academic institutions and professional colleges, various local health authorities and epidemiological surveillance programs from neighbouring countries, as well as data available through international agencies. Findings Between 2000-2015 Venezuela witnessed a 365% increase malaria cases followed by a 68% increase (319,765 cases) in late 2017. Neighbouring countries such as Brazil have reported an escalating trend of imported cases from Venezuelan from 1,538 (2014) to 3,129 (2017). Active Chagas disease transmission is reported with seroprevalence in children (<10 years) as high as 12.5% in one community tested (N=64). There has been a nine-fold rise in the mean incidence of dengue between 1990 to 2016. Estimated rates of chikungunya and Zika are 6,975 and 2,057 cases per 100,000 population, respectively, during their epidemic peaks. Interpretation The re-emergence of many arthropod-borne endemic diseases has set in place an epidemic of unprecedented proportions, not only in Venezuela but in the region. Data presented here demonstrates the complex determinants of this situation. National, regional and global authorities must take action to address these worsening epidemics and prevent their expansion beyond Venezuelan borders.
BackgroundRegardless of the growing interest in detecting population structures in malarial parasites, there have been limited discussions on how to use this concept in control programmes. In such context, the effects of the parasite population structures will depend on interventions’ spatial or temporal scales. This investigation explores the problem of identifying genetic markers, in this case microsatellites, to unveil Plasmodium genetic structures that could affect decisions in the context of elimination. The study was performed in a low-transmission area, which offers a good proxy to better understand problems associated with surveillance at the final stages of malaria elimination.MethodsPlasmodium vivax samples collected in Tumeremo, Venezuela, between March 2003 and November 2004 were analysed. Since Plasmodium falciparum also circulates in many low endemic areas, P. falciparum samples from the same locality and time period were included for comparison. Plasmodium vivax samples were assayed for an original set of 25 microsatellites and P. falciparum samples were assayed for 12 microsatellites.ResultsNot all microsatellite loci assayed offered reliable local data. A complex temporal-cluster dynamics is found in both P. vivax and P. falciparum. Such dynamics affect the numbers and the type of microsatellites required for identifying individual parasites or parasite clusters when performing cross-sectional studies. The minimum number of microsatellites required to differentiate circulating P. vivax clusters differs from the minimum number of hyper-variable microsatellites required to distinguish individuals within these clusters. Regardless the extended number of microsatellites used in P. vivax, it was not possible to separate all individual infections.ConclusionsMolecular surveillance has great potential; however, it requires preliminary local studies in order to properly interpret the emerging patterns in the context of elimination. Clonal expansions and clusters turnovers need to be taken into account when using molecular markers. Those affect the number and type of microsatellite markers, as well as, the expected genetic patterns in the context of operational investigations. By considering the local dynamics, elimination programmes could cost-effectively use molecular markers. However, population level studies need to consider the local limitations of a given set of loci in terms of providing epidemiologically relevant information.
Recent studies indicated that sensitive parasites could increase in frequency in a population when drugs are removed, suggesting that the life span of affordable antimalarial drugs could be expanded. We studied 97 samples from Bolivar State, Venezuela, an area where sulfadoxine-pyrimethamine (SP) has not been used for 8 years due to its ineffectiveness. We characterized point mutations in two genes that have been implicated in resistance to SP, dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps). We also assayed neutral microsatellite markers around the dhfr (chromosome 4) and dhps (chromosome 8) genes and on chromosomes 2 and 3 to track the origin and spread of resistant alleles. We found that drug-resistant SP mutants are fixed in the population. Two genotypes were present in the samples, dhfr(50R/51I/108N) dhps(437G/540E/581G) (90.7%) and dhfr(51I/108N) dhps(437G/581G) (9.3%). We show a single microsatellite haplotype for all of the dhfr and dhps alleles, and the alleles at the microsatellite loci are different from those present in Africa. Thus, in these samples from Venezuela, there is a single origin for both dhfr and dhps SP-resistant alleles, and these alleles originated independently of those characterized from Africa. Furthermore, this is the first report of a "hitchhiking effect" on the genetic variation around dhps due to selection by SP using an extensive set of microsatellite markers. Our results indicate that, in areas where there is limited gene flow, the fixation of drug-resistant parasites in the population is stable, even after drug selection is relaxed.The emergence of drug-resistant Plasmodium falciparum is a serious public health problem in many countries where malaria is endemic (7, 28). Sulfadoxine-pyrimethamine (SP) is an antifolate drug commonly used to treat P. falciparum infections because of its ease of administration, affordability, and efficacy. Unfortunately, resistance to SP has been documented in many parts of the world, compromising the use of this drug for treating uncomplicated P. falciparum malaria.SP acts as an inhibitor of the P. falciparum folic acid pathway, and point mutations in the genes encoding dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) have been implicated in SP resistance (9). The dhfr(S108N) point mutation and additional mutations at codons 50, 51, 59, and 164 act synergistically to increase resistance to pyrimethamine (4, 21). Similarly, mutations at dhps codons 436, 437, 540, 581, and 613 act synergistically to increase the level of resistance to sulfadoxine (7).Recent studies following the frequency of chloroquine-resistant parasites over time showed that sensitive parasites could increase in frequency soon after the drug pressure on the parasite population was decreased (13). These results suggest that, with appro-
Plasmodium vivax is the most prevalent human malaria parasite in the Americas. Previous studies have contrasted the genetic diversity of parasite populations in the Americas with those in Asia and Oceania, concluding that New World populations exhibit low genetic diversity consistent with a recent introduction. Here we used an expanded sample of complete mitochondrial genome sequences to investigate the diversity of P. vivax in the Americas as well as in other continental populations. We show that the diversity of P. vivax in the Americas is comparable to that in Asia and Oceania, and we identify several divergent clades circulating in South America that may have resulted from independent introductions. In particular, we show that several haplotypes sampled in Venezuela and northeastern Brazil belong to a clade that diverged from the other P. vivax lineages at least 30,000 years ago, albeit not necessarily in the Americas. We propose that, unlike in Asia where human migration increases local genetic diversity, the combined effects of the geographical structure and the low incidence of vivax malaria in the Americas has resulted in patterns of low local but high regional genetic diversity. This could explain previous views that P. vivax in the Americas has low genetic diversity because these were based on studies carried out in limited areas. Further elucidation of the complex geographical pattern of P. vivax variation will be important both for diversity assessments of genes encoding candidate vaccine antigens and in the formulation of control and surveillance measures aimed at malaria elimination.
Accurate and rapid diagnosis of malaria infections is crucial for implementing species-appropriate treatment and saving lives. Molecular diagnostic tools are the most accurate and sensitive method of detecting Plasmodium, differentiating between Plasmodium species, and detecting subclinical infections. Despite available whole-genome sequence data for Plasmodium falciparum and P. vivax, the majority of PCR-based methods still rely on the 18S rRNA gene targets. Historically, this gene has served as the best target for diagnostic assays. However, it is limited in its ability to detect mixed infections in multiplex assay platforms without the use of nested PCR. New diagnostic targets are needed. Ideal targets will be species specific, highly sensitive, and amenable to both single-step and multiplex PCRs. We have mined the genomes of P. falciparum and P. vivax to identify species-specific, repetitive sequences that serve as new PCR targets for the detection of malaria. We show that these targets (Pvr47 and Pfr364) exist in 14 to 41 copies and are more sensitive than 18S rRNA when utilized in a single-step PCR. Parasites are routinely detected at levels of 1 to 10 parasites/l. The reaction can be multiplexed to detect both species in a single reaction. We have examined 7 P. falciparum strains and 91 P. falciparum clinical isolates from Tanzania and 10 P. vivax strains and 96 P. vivax clinical isolates from Venezuela, and we have verified a sensitivity and specificity of ϳ100% for both targets compared with a nested 18S rRNA approach. We show that bioinformatics approaches can be successfully applied to identify novel diagnostic targets and improve molecular methods for pathogen detection. These novel targets provide a powerful alternative molecular diagnostic method for the detection of P. falciparum and P. vivax in conventional or multiplex PCR platforms.
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