Clinically silent Plasmodium vivax infections in native Amazonians of northwestern Brazil: acquired immunity or low parasite virulence?

BACKGROUND: Malaria remains common among native Amazonians, challenging Brazil's elimination efforts. OBJECTIVES: We examined the epidemiology of malaria in riverine populations of the country's main hotspot - the upper Juruá Valley in Acre state, close to the Brazil-Peru border, where Plasmodium vivax accounts for > 80% of cases. METHODS: Participants (n = 262) from 10 villages along the Azul River were screened for malaria parasites by microscopy and genus-specific, cytochrome b (cytb) gene-based polymerase chain reaction. Positive samples were further tested with quantitative TaqMan assays targeting P. vivax- and P. falciparum-specific cytb domains. We used multiple logistic regression analysis to identify independent correlates of P. vivax infection. FINDINGS: Microscopy detected only one P. vivax and two P. falciparum infections. TaqMan assays detected 33 P. vivax infections (prevalence, 11.1%), 78.1% of which asymptomatic, with a median parasitaemia of 34/mL. Increasing age, male sex and use of insecticide-treated bed nets were significant predictors of elevated P. vivax malaria risk. Children and adults were similarly likely to remain asymptomatic once infected. MAIN CONCLUSIONS: Our findings are at odds with the hypothesis of age-related clinical immunity in native Amazonians. The low virulence of local parasites is suggested as an alternative explanation for subclinical infections in isolated populations.

Apical membrane protein 1-specific antibody profile and temporal changes in peripheral blood B-cell populations in Plasmodium vivax malaria.

Plasmodium falciparum-specific antibodies tend to be short-lived, but their cognate memory B cells (MBCs) circulate in the peripheral blood of exposed subjects for several months or years after the last infection. However, the time course of antigen-specific antibodies and B-cell responses to the relatively neglected parasite Plasmodium vivax remains largely unexplored. Here, we showed that uncomplicated vivax malaria elicits short-lived antibodies but long-lived MBC responses to a major blood-stage P vivax antigen, apical membrane protein 1 (PvAMA-1), in subjects exposed to declining malaria transmission in the Amazon Basin of Brazil. We found that atypical (CD19+ CD10- CD21- CD27- ) MBCs, which appear to share a common precursor with classical MBCs but are unable to differentiate into antibody-secreting cells, significantly outnumbered classical MBCs by 5:1 in the peripheral blood of adult subjects currently or recently infected with P vivax and by 3:1 in healthy residents in the same endemic communities. We concluded that malaria can drive classical MBCs to differentiate into functionally impaired MBCs not only in subjects repeatedly exposed to P falciparum, but also in subjects living in areas with low levels of P vivax transmission in the Amazon, leading to an impaired B-cell memory that may affect both naturally acquired and vaccine-induced immunity.

Hepatitis A and E seroprevalence and associated risk factors: a community-based cross-sectional survey in rural Amazonia.

BACKGROUND: Hepatitis A virus (HAV) and hepatitis E virus (HEV) are both transmitted by the faecal-oral route, and represent common causes of acute hepatitis in developing countries. The endemicity of HAV infection has shifted from high to moderate in Brazil. Human cases of HEV infection seem to be rare, although the virus has been detected in swine livestock and effluents of slaughterhouses. This study was to determine the epidemiology of hepatitis A and E in one of the largest agricultural settlements in the Amazon Basin of Brazil. METHODS: Serum samples collected from 397 individuals aged between 5 and 90 years during a population-based cross-sectional survey were tested for anti-HAV and anti-HEV antibodies. Associated risk factors and spatial clustering of HAV and HEV seropositivity were also analyzed. RESULTS: The overall rate of HAV seropositivity was 82.9% (95% confidence interval (CI), 79.2-86.6%). Multilevel logistic regression analysis identified increasing age (in years; odds ratio (OR), 1.097; 95% CI, 1.050-1.147; P < 0.001) and crowding (OR, 1.603; 95% CI, 1.054-2.440; P = 0.028) as significant risk factors for HAV seropositivity. Anti-HEV IgG was detected in 50/388 settlers (12.9%, 95% CI, 9.5-16.2%). Anti-HEV IgM was detected in 7/43 (16.3%) anti-IgG positive samples, and 4 of them had a confirmed result by immunoblot. Increasing age was the only significant determinant of HEV seropositivity (OR, 1.033; 95% CI, 1.016-1.050; P < 0.001). No significant spatial clustering of HAV and HEV seropositivity was detected in the area. CONCLUSIONS: Both HAV and HEV are endemic, with differing rates of infection in children and adults in this rural setting of the Brazilian Amazon. Anti-HEV prevalence was considerably higher than those previously reported in Brazil. The detection of HEV- specific IgM antibodies in four asymptomatic individuals is highly suggestive of the circulation of HEV in this rural population.

Emerging Plasmodium vivax resistance to chloroquine in South America: an overview.

The global emergence of Plasmodium vivax strains resistant to chloroquine (CQ) since the late 1980s is complicating the current international efforts for malaria control and elimination. Furthermore, CQ-resistant vivax malaria has already reached an alarming prevalence in Indonesia, East Timor and Papua New Guinea. More recently, in vivo studies have documented CQ-resistant P. vivax infections in Guyana, Peru and Brazil. Here, we summarise the available data on CQ resistance across P. vivax-endemic areas of Latin America by combining published in vivo and in vitro studies. We also review the current knowledge regarding the molecular mechanisms of CQ resistance in P. vivax and the prospects for developing and standardising reliable molecular markers of drug resistance. Finally, we discuss how the Worldwide Antimalarial Resistance Network, an international collaborative effort involving malaria experts from all continents, might contribute to the current regional efforts to map CQ-resistant vivax malaria in South America.

Dynamics of IgM and IgG Antibody Response Profile against Linear B-Cell Epitopes from Exoerythrocytic (CelTOS and TRAP) and Erythrocytic (CyRPA) Phases of Plasmodium vivax: Follow-Up Study.

Malaria is a serious health problem worldwide affecting mainly children and socially vulnerable people. The biological particularities of P. vivax, such as the ability to generate dormant liver stages, the rapid maturation of gametocytes, and the emergence of drug resistance, have contributed to difficulties in disease control. In this context, developing an effective vaccine has been considered a fundamental tool for the efficient control and/or elimination of vivax malaria. Although recombinant proteins have been the main strategy used in designing vaccine prototypes, synthetic immunogenic peptides have emerged as a viable alternative for this purpose. Considering, therefore, that in the Brazilian endemic population, little is known about the profile of the humoral immune response directed to synthetic peptides that represent different P. vivax proteins, the present work aimed to map the epitope-specific antibodies' profiles to synthetic peptides representing the linear portions of the ookinete and sporozoite cell passage protein (CelTOS), thrombospondin-related adhesive protein (TRAP), and cysteine-rich protective antigen (CyRPA) proteins in the acute (AC) and convalescent phases (Conv30 and Conv180 after infection) of vivax malaria. The results showed that the studied subjects responded to all proteins for at least six months following infection. For IgM, a few individuals (3-21%) were positive during the acute phase of the disease; the highest frequencies were observed for IgG (28-57%). Regarding the subclasses, IgG2 and IgG3 stood out as the most prevalent for all peptides. During the follow-up, the stability of IgG was observed for all peptides. Only one significant positive correlation was observed between IgM and exposure time. We conclude that for all the peptides, the immunodominant epitopes are recognized in the exposed population, with similar frequency and magnitude. However, if the antibodies detected in this study are potential protectors, this needs to be investigated.

Adolescent pregnancy in Cruzeiro do Sul, Acre, Brazil: socioeconomic characteristics, prenatal and obstetric care. / Parturientes adolescentes em Cruzeiro do Sul, Acre, Brasil: características socioeconômicas e obstétricas.

The present study aimed to investigate the socioeconomic and obstetric characteristics of adolescent mothers and the complications they cause to maternal and neonatal health. This baseline data analysis of the MINA-Brazil birth cohort was conducted in the municipality of Cruzeiro do Sul, state of Acre, Brazil. The chi-square test was used to compare characteristics of adolescent and adult postpartum women, and multiple Poisson regression models with robust variance were used to assess associated factors. Among the postpartum women, 26.2% (95%CI: 24.0-28.4) were adolescents. Factors associated with childbirth in adolescence included: nine years or less of schooling (adjPR:1.36; 95%CI: 1.14-1.61), belongs to the lowest quartiles of the wealth index (1st quartile: adjPR:1.40; 95%CI: 1.08-1.80) (2nd quartile: adjPR:1.37; 95%CI: 1.08-1.74), primigravidae (adjPR:3.69; 95%CI: 2.98-4.57), low pre-pregnancy BMI (adjPR:1.28; CI95%: 1.04-1.57), urinary tract infection during pregnancy (adjPR:1.25; CI95%: 1.07-1.46) and less than six prenatal consultations (adjPR:1.42; 95%CI: 1.21-1.66). Poverty, little schooling, primigravidae, low pre-pregnancy BMI, urinary tract infection during pregnancy and few prenatal consultations were associated with childbirth during adolescence in a municipality in the Northern region of Brazil.

O objetivo do estudo foi investigar as características socioeconômicas e obstétricas de parturientes adolescentes e suas complicações sobre a saúde materna e neonatal. Trata-se de uma análise de dados da linha de base da coorte de nascimentos MINA-Brasil conduzida no município de Cruzeiro do Sul, estado do Acre. Utilizou-se teste qui-quadrado para comparar características das puérperas adolescentes com as adultas e modelos múltiplos de regressão de Poisson com variância robusta para avaliar fatores associados. Entre as puérperas estudadas, 26,2% (IC95%: 24,0-28,4) eram adolescentes. Os fatores associados ao parto na adolescência foram ter nove anos ou menos de estudo (RPaj:1,36; IC95%: 1,14-1,61), pertencer aos menores quartis do índice de riqueza (1° quartil: RPaj:1,40; IC95%: 1,08-1,80) (2° quartil: RPaj:1,37; IC95%: 1,08-1,74), ser primigesta (RPaj:3,69; IC95%: 2,98-4,57), baixo IMC pré-gestacional (RPaj:1,28; IC95%: 1,04-1,57), infecção urinária na gravidez (RPaj:1,25; IC95%: 1,07-1,46) e menos de seis consultas de pré-natal (RPaj:1,42; IC95%: 1,21-1,66). Pobreza, baixa escolaridade, primigestação, baixo IMC pré-gestacional, infecção urinária na gestação e menor número de consultas de pré-natal foram associados ao parto na adolescência em município da região Norte do Brasil.

Reduced polymorphism of Plasmodium vivax early transcribed membrane protein (PvETRAMP) 11.2.

BACKGROUND: ETRAMP11.2 (PVX_003565) is a well-characterized protein with antigenic potential. It is considered to be a serological marker for diagnostic tools, and it has been suggested as a potential vaccine candidate. Despite its immunological relevance, the polymorphism of the P. vivax ETRAMP11.2 gene (pvetramp11.2) remains undefined. The genetic variability of an antigen may limit the effectiveness of its application as a serological surveillance tool and in vaccine development and, therefore, the aim of this study was to investigate the genetic diversity of pvetramp11.2 in parasite populations from Amazonian regions and worldwide. We also evaluated amino acid polymorphism on predicted B-cell epitopes. The low variability of the sequence encoding PvETRAMP11.2 protein suggests that it would be a suitable marker in prospective serodiagnostic assays for surveillance strategies or in vaccine design against P. vivax malaria. METHODS: The pvetramp11.2 of P. vivax isolates collected from Brazil (n = 68) and Peru (n = 36) were sequenced and analyzed to assess nucleotide polymorphisms, allele distributions, population differentiation, genetic diversity and signature of selection. In addition, sequences (n = 104) of seven populations from different geographical regions were retrieved from the PlasmoDB database and included in the analysis to study the worldwide allele distribution. Potential linear B-cell epitopes and their polymorphisms were also explored. RESULTS: The multiple alignments of 208 pvetramp11.2 sequences revealed a low polymorphism and a marked geographical variation in allele diversity. Seven polymorphic sites and 11 alleles were identified. All of the alleles were detected in isolates from the Latin American region and five alleles were detected in isolates from the Southeast Asia/Papua New Guinea (SEA/PNG) region. Three alleles were shared by all Latin American populations (H1, H6 and H7). The H1 allele (reference allele from Salvador-1 strain), which was absent in the SEA/PNG populations, was the most represented allele in populations from Brazil (54%) and was also detected at high frequencies in populations from all other Latin America countries (range: 13.0% to 33.3%). The H2 allele was the major allele in SEA/PNG populations, but was poorly represented in Latin America populations (only in Brazil: 7.3%). Plasmodium vivax populations from Latin America showed a marked inter-population genetic differentiation (fixation index [Fst]) in contrast to SEA/PNG populations. Codon bias measures (effective number of codons [ENC] and Codon bias index [CBI]) indicated preferential use of synonymous codons, suggesting selective pressure at the translation level. Only three amino acid substitutions, located in the C-terminus, were detected. Linear B-cell epitope mapping predicted two epitopes in the Sal-1 PvETRAMP11.2 protein, one of which was fully conserved in all of the parasite populations analyzed. CONCLUSIONS: We provide an overview of the allele distribution and genetic differentiation of ETRAMP11.2 antigen in P. vivax populations from different endemic areas of the world. The reduced polymorphism and the high degree of protein conservation supports the application of PvETRAMP11.2 protein as a reliable antigen for application in serological assays or vaccine design. Our findings provide useful information that can be used to inform future study designs.

An update on pharmacogenetic factors influencing the metabolism and toxicity of artemisinin-based combination therapy in the treatment of malaria.

INTRODUCTION: Artemisinin-based combination therapies (ACTs) are recommended first-line antimalarials for uncomplicated Plasmodium falciparum malaria. Pharmacokinetic/pharmacodynamic variation associated with ACT drugs and their effect is documented. It is accepted to an extent that inter-individual variation is genetically driven, and should be explored for optimized antimalarial use. AREAS COVERED: We provide an update on the pharmacogenetics of ACT antimalarial disposition. Beyond presently used antimalarials, we also refer to information available for the most notable next-generation drugs under development. The bibliographic approach was based on multiple Boolean searches on PubMed covering all recent publications since our previous review. EXPERT OPINION: The last 10 years have witnessed an increase in our knowledge of ACT pharmacogenetics, including the first clear examples of its contribution as an exacerbating factor for drug-drug interactions. This knowledge gap is still large and is likely to widen as a new wave of antimalarial drug is looming, with few studies addressing their pharmacogenetics. Clinically useful pharmacogenetic markers are still not available, in particular, from an individual precision medicine perspective. A better understanding of the genetic makeup of target populations can be valuable for aiding decisions on mass drug administration implementation concerning region-specific antimalarial drug and dosage options.

Molecular markers and genetic diversity of Plasmodium vivax.

Enhanced understanding of the transmission dynamics and population genetics for Plasmodium vivax is crucial in predicting the emergence and spread of novel parasite phenotypes with major public health implications, such as new relapsing patterns, drug resistance and increased virulence. Suitable molecular markers are required for these population genetic studies. Here, we focus on two groups of molecular markers that are commonly used to analyse natural populations of P. vivax. We use markers under selective pressure, for instance, antigen-coding polymorphic genes, and markers that are not under strong natural selection, such as most minisatellite and microsatellite loci. First, we review data obtained using genes encoding for P. vivax antigens: circumsporozoite protein, merozoite surface proteins 1 and 3α, apical membrane antigen 1 and Duffy binding antigen. We next address neutral or nearly neutral molecular markers, especially microsatellite loci, providing a complete list of markers that have already been used in P. vivax populations studies. We also analyse the microsatellite loci identified in the P. vivax genome project. Finally, we discuss some practical uses for P. vivax genotyping, for example, detecting multiple-clone infections and tracking the geographic origin of isolates.

A Retrospective Survey of Rodent-borne Viruses in Rural Populations of Brazilian Amazon.

INTRODUCTION: The Amazon tropical rainforest has the most dense and diverse ecosystem worldwide. A few studies have addressed rodent-borne diseases as potential hazards to humans in this region. METHODS: A retrospective survey was conducted using enzyme-linked immunosorbent assay for detecting mammarenavirus and orthohantavirus antibodies in 206 samples collected from rural settlers of the Brazilian Western Amazonian region. RESULTS: Six (2.91%) individuals in the age group of 16 to 36 years were found to possess antibodies against mammarenavirus. CONCLUSION: Evidence of previous exposure to mammarenavirus in the rural population points to its silent circulation in this region.

Parturientes adolescentes em Cruzeiro do Sul, Acre, Brasil: características socioeconômicas e obstétricas / Adolescent pregnancy in Cruzeiro do Sul, Acre, Brazil: socioeconomic characteristics, prenatal and obstetric care

Resumo O objetivo do estudo foi investigar as características socioeconômicas e obstétricas de parturientes adolescentes e suas complicações sobre a saúde materna e neonatal. Trata-se de uma análise de dados da linha de base da coorte de nascimentos MINA-Brasil conduzida no município de Cruzeiro do Sul, estado do Acre. Utilizou-se teste qui-quadrado para comparar características das puérperas adolescentes com as adultas e modelos múltiplos de regressão de Poisson com variância robusta para avaliar fatores associados. Entre as puérperas estudadas, 26,2% (IC95%: 24,0-28,4) eram adolescentes. Os fatores associados ao parto na adolescência foram ter nove anos ou menos de estudo (RPaj:1,36; IC95%: 1,14-1,61), pertencer aos menores quartis do índice de riqueza (1° quartil: RPaj:1,40; IC95%: 1,08-1,80) (2° quartil: RPaj:1,37; IC95%: 1,08-1,74), ser primigesta (RPaj:3,69; IC95%: 2,98-4,57), baixo IMC pré-gestacional (RPaj:1,28; IC95%: 1,04-1,57), infecção urinária na gravidez (RPaj:1,25; IC95%: 1,07-1,46) e menos de seis consultas de pré-natal (RPaj:1,42; IC95%: 1,21-1,66). Pobreza, baixa escolaridade, primigestação, baixo IMC pré-gestacional, infecção urinária na gestação e menor número de consultas de pré-natal foram associados ao parto na adolescência em município da região Norte do Brasil.

Abstract The present study aimed to investigate the socioeconomic and obstetric characteristics of adolescent mothers and the complications they cause to maternal and neonatal health. This baseline data analysis of the MINA-Brazil birth cohort was conducted in the municipality of Cruzeiro do Sul, state of Acre, Brazil. The chi-square test was used to compare characteristics of adolescent and adult postpartum women, and multiple Poisson regression models with robust variance were used to assess associated factors. Among the postpartum women, 26.2% (95%CI: 24.0-28.4) were adolescents. Factors associated with childbirth in adolescence included: nine years or less of schooling (adjPR:1.36; 95%CI: 1.14-1.61), belongs to the lowest quartiles of the wealth index (1st quartile: adjPR:1.40; 95%CI: 1.08-1.80) (2nd quartile: adjPR:1.37; 95%CI: 1.08-1.74), primigravidae (adjPR:3.69; 95%CI: 2.98-4.57), low pre-pregnancy BMI (adjPR:1.28; CI95%: 1.04-1.57), urinary tract infection during pregnancy (adjPR:1.25; CI95%: 1.07-1.46) and less than six prenatal consultations (adjPR:1.42; 95%CI: 1.21-1.66). Poverty, little schooling, primigravidae, low pre-pregnancy BMI, urinary tract infection during pregnancy and few prenatal consultations were associated with childbirth during adolescence in a municipality in the Northern region of Brazil.

Child health and nutrition in the Western Brazilian Amazon: population-based surveys in two counties in Acre State.

The article presents prevalence rates for malnutrition, intestinal parasitic infections, anemia, and iron deficiency in under-five children in a population-based cross-sectional survey performed in the urban area of two counties in the Western Brazilian Amazon, Assis Brasil (n = 200) and Acrelandia (n = 477). Available data included: (a) weight and height measurements, standardized as z-scores using the 1977 NCHS reference population, (b) diagnosis of current intestinal parasitic infection, (c) blood hemoglobin levels, and (d) plasma ferritin and soluble transferrin receptor levels. Overall prevalence rates of low weight-for-height, low weight-for-age, and low height-for-age were 3.7%, 8.7%, and 7.5%, respectively, with similar figures in the two towns. Intestinal parasites were detected in 32.5% children; helminths were uncommon. Anemia and iron deficiency were diagnosed in 30.6% and 43.5% of the children, respectively. Evidence of anemia was found in only 47.6% of the children with depleted iron reserves, indicating that hemoglobin measurement alone would severely underestimate the magnitude of iron deficiency in this population. In both towns, anemia and malnutrition were significantly more prevalent among children in the lowest socioeconomic stratum.

Prevalence and spatial distribution of intestinal parasitic infections in a rural Amazonian settlement, Acre State, Brazil.

A population-based survey of the prevalence and spatial distribution of intestinal parasitism was carried out in an agricultural settlement in the Amazon Basin of Brazil (Granada, Acre State). More than half (53.4%) of the 429 stool specimens from subjects in all age groups, living in 113 households, had cysts, ova, or larvae of intestinal parasites. The most prevalent parasites were Giardia duodenalis (19.6%) and soil-transmitted helminths (12.7%); 105 (24.5%) subjects were infected with more than one species of parasite. Significant age-related differences in prevalence were only found for G. duodenalis (children < 1 year and adults > 30 years were less affected). Six households (5.3%), situated within a radius of 690m, comprised 48.1% of all subjects harboring soil-transmitted helminths in our study area. Households within this cluster were poorer and more crowded than those outside the cluster. The observed spatial clustering of infections with soil-transmitted helminths provides valuable information for the spatial targeting of sanitary interventions in this area.

Clinically silent Plasmodium vivax infections in native Amazonians of northwestern Brazil: acquired immunity or low parasite virulence?

BACKGROUND Malaria remains common among native Amazonians, challenging Brazil′s elimination efforts. OBJECTIVES We examined the epidemiology of malaria in riverine populations of the country′s main hotspot - the upper Juruá Valley in Acre state, close to the Brazil-Peru border, where Plasmodium vivax accounts for > 80% of cases. METHODS Participants (n = 262) from 10 villages along the Azul River were screened for malaria parasites by microscopy and genus-specific, cytochrome b (cytb) gene-based polymerase chain reaction. Positive samples were further tested with quantitative TaqMan assays targeting P. vivax- and P. falciparum-specific cytb domains. We used multiple logistic regression analysis to identify independent correlates of P. vivax infection. FINDINGS Microscopy detected only one P. vivax and two P. falciparum infections. TaqMan assays detected 33 P. vivax infections (prevalence, 11.1%), 78.1% of which asymptomatic, with a median parasitaemia of 34/mL. Increasing age, male sex and use of insecticide-treated bed nets were significant predictors of elevated P. vivax malaria risk. Children and adults were similarly likely to remain asymptomatic once infected. MAIN CONCLUSIONS Our findings are at odds with the hypothesis of age-related clinical immunity in native Amazonians. The low virulence of local parasites is suggested as an alternative explanation for subclinical infections in isolated populations.

The Acre Project: the epidemiology of malaria and arthropod-borne virus infections in a rural Amazonian population.

The authors describe the baseline malaria prevalence and arbovirus seroprevalence among 467 subjects in an ongoing cohort study in rural Amazonia. Most subjects (72.2%) reported one or more previous episodes of malaria, and 15.6% had been hospitalized for malaria, but only 3.6% of individuals five years or older had malaria parasites detected by microscopy (10 with Plasmodium vivax and 4 with P. falciparum). Antibodies to Alphavirus, Orthobunyavirus, and/or Flavivirus were detected by hemagglutination inhibition (HI) in 42.6% of subjects aged five years or older, with a higher seropositivity rate among males (49.2%) than females (36.2%). Since 98.9% of subjects had been immunized for yellow fever, the presence of cross-reactive antibodies to dengue and other Flaviviruses cannot be ruled out, but at least 12 subjects (3.3%) with IgM antibodies to dengue virus detected by ELISA had a putative recent exposure to this virus.

A Retrospective Survey of Rodent-borne Viruses in Rural Populations of Brazilian Amazon

Abstract INTRODUCTION: The Amazon tropical rainforest has the most dense and diverse ecosystem worldwide. A few studies have addressed rodent-borne diseases as potential hazards to humans in this region. METHODS: A retrospective survey was conducted using enzyme-linked immunosorbent assay for detecting mammarenavirus and orthohantavirus antibodies in 206 samples collected from rural settlers of the Brazilian Western Amazonian region. RESULTS: Six (2.91%) individuals in the age group of 16 to 36 years were found to possess antibodies against mammarenavirus. CONCLUSION: Evidence of previous exposure to mammarenavirus in the rural population points to its silent circulation in this region.

Parasite virulence, co-infections and cytokine balance in malaria.

Strong early inflammatory responses followed by a timely production of regulatory cytokines are required to control malaria parasite multiplication without inducing major host pathology. Here, we briefly examine the homeostasis of inflammatory responses to malaria parasite species with varying virulence levels and discuss how co-infections with bacteria, viruses, and helminths can modulate inflammation, either aggravating or alleviating malaria-related morbidity.

Evidence-based public health and prospects for malaria control in Brazil.

Despite intensive control efforts over the past decades, Brazil still accounts for more than 50% of the malaria burden in the Americas and the Caribbean, with 458,041 slide-confirmed cases reported countrywide in 2007. The reason malaria has proved so difficult to control in this middle-income country with a reasonable health infrastructure remains unclear. Here we examine whether four strategies that were largely successful in other countries (aggressive active case detection, improved anti-relapse therapy for P. vivax infections, distribution of insecticide-treated bed nets, and selective house spraying with residual insecticides) are likely to work in Brazil. We review evidence from field and laboratory studies and identify gaps in our knowledge that require further investigation with well-designed large-scale trials.

Emerging Plasmodium vivax resistance to chloroquine in South America: an overview

The global emergence of Plasmodium vivax strains resistant to chloroquine (CQ) since the late 1980s is complicating the current international efforts for malaria control and elimination. Furthermore, CQ-resistant vivax malaria has already reached an alarming prevalence in Indonesia, East Timor and Papua New Guinea. More recently, in vivo studies have documented CQ-resistant P. vivax infections in Guyana, Peru and Brazil. Here, we summarise the available data on CQ resistance across P. vivax-endemic areas of Latin America by combining published in vivo and in vitro studies. We also review the current knowledge regarding the molecular mechanisms of CQ resistance in P. vivax and the prospects for developing and standardising reliable molecular markers of drug resistance. Finally, we discuss how the Worldwide Antimalarial Resistance Network, an international collaborative effort involving malaria experts from all continents, might contribute to the current regional efforts to map CQ-resistant vivax malaria in South America.

Recurrent parasitemias and population dynamics of Plasmodium vivax polymorphisms in rural Amazonia.

Clinical trials documented alarming post-treatment Plasmodium vivax recurrence rates caused by recrudescence of surviving asexual blood stages, relapse from hypnozoites, or new infections. Here we describe high rates of P. vivax recurrence (26-40% 180 days after treatment) in two cohorts of rural Amazonians exposed to low levels of malaria transmission after a vivax malaria episode treated with chloroquine-primaquine. Microsatellite analysis of 28 paired acute infection and recurrence parasites showed only two pairs of identical haplotypes (consistent with recrudescences or reactivation of homologous hypnozoites) and four pairs of related haplotypes (sharing alleles at 11-13 of 14 microsatellites analyzed). Local isolates of P. vivax were extraordinarily diverse and rarely shared the same haplotype, indicating that frequent recurrences did not favor the persistence or reappearance of clonal lineages of parasites in the population. This fast haplotype replacement rate may represent the typical population dynamics of neutral polymorphisms in parasites from low-endemicity areas.