Most rapid diagnostic tests for
Plasmodium falciparum
malaria target the Histidine-Rich Proteins 2 and 3 (HRP2 and HRP3). Deletions of the
hrp2
and
hrp3
genes result in false-negative tests and are a ...threat for malaria control. A novel assay for molecular surveillance of
hrp2
/
hrp3
deletions was developed based on droplet digital PCR (ddPCR). The assay quantifies
hrp2
,
hrp3
, and a control gene with very high accuracy. The theoretical limit of detection was 0.33 parasites/µl. The deletion was reliably detected in mixed infections with wild-type and
hrp2
-deleted parasites at a density of >100 parasites/reaction. For a side-by-side comparison with the conventional nested PCR (nPCR) assay, 248 samples were screened in triplicate by ddPCR and nPCR. No deletions were observed by ddPCR, while by nPCR
hrp2
deletion was observed in 8% of samples. The ddPCR assay was applied to screen 830 samples from Kenya, Zanzibar/Tanzania, Ghana, Ethiopia, Brazil, and Ecuador. Pronounced differences in the prevalence of deletions were observed among sites, with more
hrp3
than
hrp2
deletions. In conclusion, the novel ddPCR assay minimizes the risk of false-negative results (i.e.,
hrp2
deletion observed when the sample is wild type), increases sensitivity, and greatly reduces the number of reactions that need to be run.
Emerging antimalarial drug resistance may undermine current efforts to control and eliminate Plasmodium vivax, the most geographically widespread yet neglected human malaria parasite. Endemic ...countries are expected to assess regularly the therapeutic efficacy of antimalarial drugs in use in order to adjust their malaria treatment policies, but proper funding and trained human resources are often lacking to execute relatively complex and expensive clinical studies, ideally complemented by ex vivo assays of drug resistance. Here we review the challenges for assessing in vivo P. vivax responses to commonly used antimalarials, especially chloroquine and primaquine, in the presence of confounding factors such as variable drug absorption, metabolism and interaction, and the risk of new infections following successful radical cure. We introduce a simple modeling approach to quantify the relative contribution of relapses and new infections to recurring parasitemias in clinical studies of hypnozoitocides. Finally, we examine recent methodological advances that may render ex vivo assays more practical and widely used to confirm P. vivax drug resistance phenotypes in endemic settings and review current approaches to the development of robust genetic markers for monitoring chloroquine resistance in P. vivax populations.
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•Plasmodium vivax resistance to chloroquine may undermine malaria elimination efforts.•Plasmodium vivax resistance to schizontocides has been mostly monitored in therapeutic efficacy studies.•In vivo studies to determine the anti-relapse efficacy of primaquine are challenging to design and execute.•Ex vivo assays to determine Plasmodium vivax resistance to schizontocides remain limited to research settings.•Robust molecular markers to monitor Plasmodium vivax drug resistance are currently lacking.
Plasmodium vivax is a neglected human malaria parasite that causes significant morbidity in the Americas, the Middle East, Asia, and the Western Pacific. Population genomic approaches remain little ...explored to map local and regional transmission pathways of P. vivax across the main endemic sites in the Americas, where great progress has been made towards malaria elimination over the past decades.
We analyze 38 patient-derived P. vivax genome sequences from Mâncio Lima (ML)-the Amazonian malaria hotspot next to the Brazil-Peru border-and 24 sequences from two other sites in Acre State, Brazil, a country that contributes 23% of malaria cases in the Americas. We show that the P. vivax population of ML is genetically diverse (π = 4.7 × 10-4), with a high polymorphism particularly in genes encoding proteins putatively involved in red blood cell invasion. Paradoxically, however, parasites display strong genome-wide linkage disequilibrium, being fragmented into discrete lineages that are remarkably stable across time and space, with only occasional recombination between them. Using identity-by-descent approaches, we identified a large cluster of closely related sequences that comprises 16 of 38 genomes sampled in ML over 26 months. Importantly, we found significant ancestry sharing between parasites at a large geographic distance, consistent with substantial gene flow between regional P. vivax populations.
We have characterized the sustained expansion of highly inbred P. vivax lineages in a malaria hotspot that can seed regional transmission. Potential source populations in hotspots represent a priority target for malaria elimination in the Amazon.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigated linear growth and weight attained among 772 children at 10-15 months of age in the first population-based birth cohort in the Brazilian Amazon. Sociodemographic, maternal and birth ...characteristics were collected in interviews soon after birth at baseline. Anthropometric evaluation was conducted at 10-15 months. Multiple linear regression models were fitted for length-for-age (LAZ) and body mass index (BMI)-for-age Z scores (BAZ), considering a hierarchical conceptual framework with determinants at distal, intermediate and proximal levels, with adjustment for the child's sex and age. Mean LAZ and BAZ were 0.31 (SD: 1.13) and 0.35 (SD: 1.06), respectively. Overall, 2.2% of children were stunted and 6.6% overweight. Among socioeconomic factors, household wealth index was positively associated with LAZ (p for trend = 0.01), while children whose families received assistance from the Bolsa Família conditional cash transfer program were 0.16 Z score thinner (95% CI: -0.31, -0.00). Maternal height and BMI were positively associated with both LAZ and BAZ at 10-15 months of age (p for trend <0.001). Child's size at birth was positively related with LAZ (p<0.001 for both birth weight and length). BAZ was 0.34 (95% CI: 0.24, 0.44) higher, but 0.11 lower (95% CI: -0.21, -0.02), for each increase in 1 Z score of birth weight and length, respectively. Children with at least one reported malaria episode within the first year of life were 0.58 (95% CI: -1.05, -0.11) Z score shorter. Socioeconomic and intergenerational factors were consistently associated with LAZ and BAZ at 10-15 months of age. The occurrence of malaria was detrimental to linear growth. In a malaria endemic region, reduction of inequalities and disease burden over the first 1,000 days of life is essential for taking advantage of a critical window of opportunity that can redirect child growth trajectories toward better health and nutrition conditions in the long term.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The evolution of malaria in Brazil, its morbidity, the malaria control
programs, and the new challenges for these programs in the light of the
emergence of asymptomatic infection in the Amazon region ...of Brazil were
reviewed. At least six Brazilian research groups have demonstrated that
asymptomatic infection by Plasmodium is an important impediment to
malaria control, among mineral prospectors in Mato Grosso and riverside
communities in Rondônia and, in our group, in the middle and upper
reaches of the Negro river, in the state of Amazonas. Likewise, other
researchers have studied the problem among indigenous communities in
the Colombian, Peruvian, and Venezuelan parts of the Amazon basin,
adjacent to Brazil. The frequency of positive results from the
polymerase chain reaction (PCR) among asymptomatic individuals has
ranged from 20.4 to 49.5%, and the presence of Plasmodium in the thick
blood smears, from 4.2 to 38.5%. Infection with Anopheles darlingi has
also been demonstrated by xenodiagnosis among asymptomatic patients
with positive PCR results. If a mean of 25% is taken for the
asymptomatic infection caused by Plasmodium sp. in the Amazon region of
Brazil, malaria control will be difficult to achieve in that region
with the measures currently utilized for such control.
Low-density and asymptomatic Plasmodium vivax infections remain largely undetected and untreated and may contribute significantly to malaria transmission in the Amazon.
We analysed individual ...participant data from population-based surveys that measured P vivax prevalence by microscopy and polymerase chain reaction (PCR) between 2002 and 2015 and modelled the relationship between parasite density and infectiousness to vectors using membrane feeding assay data. We estimated the proportion of sub-patent (i.e., missed by microscopy) and asymptomatic P vivax infections and examined how parasite density relates to clinical manifestations and mosquito infection in Amazonian settings.
We pooled 24,986 observations from six sites in Brazil and Peru. P vivax was detected in 6·8% and 2·1% of them by PCR and microscopy, respectively. 58·5% to 92.6% of P vivax infections were asymptomatic and 61·2% to 96·3% were sub-patent across study sites. P vivax density thresholds associated with clinical symptoms were one order of magnitude higher in children than in adults. We estimate that sub-patent parasite carriers are minimally infectious and contribute 12·7% to 24·9% of the community-wide P vivax transmission, while asymptomatic carriers are the source of 28·2% to 79·2% of mosquito infections.
Asymptomatic P vivax carriers constitute a vast infectious reservoir that, if targeted by malaria elimination strategies, could substantially reduce malaria transmission in the Amazon. Infected children may remain asymptomatic despite high parasite densities that elicit clinical manifestations in adults.
US National Institutes of Health, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Belgium Development Cooperation.
Larvicides are typically applied to fixed and findable mosquito breeding sites, such as fish farming ponds used in commercial aquaculture, to kill immature forms and thereby reduce the size of adult ...malaria vector populations. However, there is little evidence suggesting that larviciding may suppress community-wide malaria transmission outside Africa. Here, we tested whether the biological larvicide VectoMax FG applied at monthly intervals to fish farming ponds can reduce malaria incidence in Amazonian Brazil.
This study was carried out in Vila Assis Brasil (VAB; population 1700), a peri-urban malaria hotspot in northwestern Brazil with a baseline annual parasite incidence of 553 malaria cases per 1000 inhabitants. The intervention consisted of monthly treatments with 20 kg/ha of VectoMax FG of all water-filled fish ponds in VAB (n ranging between 167 and 170) with a surface area between 20 and 8000 m
, using knapsack power mistblowers. We used single-group interrupted time-series analysis to compare monthly larval density measurements in fish ponds during a 14-month pre-intervention period (September 2017-October 2018), with measurements made during November 2018-October 2019 and shortly after the 12-month intervention (November 2019). We used interrupted time-series analysis with a comparison group to contrast the malaria incidence trends in VAB and nearby nonintervention localities before and during the intervention.
Average larval densities decreased tenfold in treated fish farming ponds, from 0.467 (95% confidence interval CI, 0.444-0.490) anopheline larvae per dip pre-intervention (September 2017-October 2018) to 0.046 (95% CI, 0.041-0.051) larvae per dip during (November 2018-October 2019) and shortly after the intervention (November 2019). Average malaria incidence rates decreased by 0.08 (95% CI, 0.04-0.11) cases per 100 person-months (P < 0.0001) during the intervention in VAB and remained nearly unchanged in comparison localities. We estimate that the intervention averted 24.5 (95% CI, 6.2-42.8) malaria cases in VAB between January and December 2019.
Regular larviciding is associated with a dramatic decrease in larval density and a modest but significant decrease in community-wide malaria incidence. Larviciding may provide a valuable complementary vector control strategy in commercial aquaculture settings across the Amazon.
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected human disease. It is endemic to the Americas and is estimated to have an economic impact, including lost productivity ...and disability, of 7 billion dollars per year on average.
To assess vulnerability to vector-borne transmission of T. cruzi in domiciliary environments within an area undergoing domiciliary vector interruption of T. cruzi in Colombia.
Multi-criteria decision analysis preference ranking method for enrichment evaluation (PROMETHEE) and geometrical analysis for interactive assistance (GAIA) methods and spatial statistics were performed on data from a socio-environmental questionnaire and an entomological survey. In the construction of multi-criteria descriptors, decision-making processes and indicators of five determinants of the CD vector pathway were summarily defined, including: (1) house indicator (HI); (2) triatominae indicator (TI); (3) host/reservoir indicator (Ho/RoI); (4) ecotope indicator (EI); and (5) socio-cultural indicator (S-CI).
Determination of vulnerability to CD is mostly influenced by TI, with 44.96% of the total weight in the model, while the lowest contribution was from S-CI, with 7.15%. The five indicators comprise 17 indices, and include 78 of the original 104 priority criteria and variables. The PROMETHEE and GAIA methods proved very efficient for prioritisation and quantitative categorisation of socio-environmental determinants and for better determining which criteria should be considered for interrupting the man-T. cruzi-vector relationship in endemic areas of the Americas. Through the analysis of spatial autocorrelation it is clear that there is a spatial dependence in establishing categories of vulnerability, therefore, the effect of neighbors' setting (border areas) on local values should be incorporated into disease management for establishing programs of surveillance and control of CD via vector.
The study model proposed here is flexible and can be adapted to various eco-epidemiological profiles and is suitable for focusing anti-T. cruzi serological surveillance programs in vulnerable human populations.
Abstract
Background
Malarial infections are often missed by microscopy, and most parasite carriers are asymptomatic in low-endemicity settings. Whether parasite detectability and its ability to ...elicit symptoms change as transmission declines remains unclear.
Methods
We performed a prospective panel survey with repeated measurements on the same participants over 12 months to investigate whether Plasmodium vivax detectability by microscopy and risk of symptoms upon infection varied during a community-wide larviciding intervention in the Amazon basin of Brazil that markedly reduced vector density. We screened 1096 to 1400 residents in the intervention site for malaria by microscopy and quantitative TaqMan assays at baseline and twice during intervention.
Results
We found that more P vivax infections than expected from their parasite densities measured by TaqMan assays were missed by microscopy as transmission decreased. At lower transmission, study participants appeared to tolerate higher P vivax loads without developing symptoms. We hypothesize that changes in the ratio between circulating parasites and those that accumulate in the bone marrow and spleen, by avoiding peripheral blood microscopy detection, account for decreased parasite detectability and lower risk of symptoms under low transmission.
Conclusions
P vivax infections are more likely to be subpatent and remain asymptomatic as malaria transmission decreases.
Plasmodium vivax detectability by microscopy and its ability to elicit symptoms decrease as transmission is reduced in the Amazon. Changes in the ratio between circulating parasites and those accumulating in the bone marrow and spleen might account for this finding.
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