Changing Clinical Epidemiology of Plasmodium vivax Malaria as Transmission Decreases: Population-Based Prospective Panel Survey in the Brazilian Amazon.

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.

The impact of hydropower dam construction on malaria incidence: Space-time analysis in the Brazilian Amazon.

During the first two decades of the 21st century, Brazil carried out massive public investments on infrastructure projects, such as large hydropower dams, with potential impact on population health. Here we characterize local malaria transmission and its potential spread during the construction of three large hydropower dams in the Brazilian Amazon. We focus on Porto Velho (PVH), in Rondônia state, where the Santo Antônio and Jirau dams were built (2008-2013), and Altamira region (ATM), in Pará state, where the construction of the Belo Monte dam took place (2011-2016). Analyzed data cover 4 years before, 6 years during, and 4 years after each dam construction. In total, we utilized malaria case notifications entered into the electronic malaria notification system of the Ministry of Health of Brazil between January 2004 and December 2020 (n = 39,977,167 malaria notifications). First, we used Interrupted Time-Series Analysis (ITSA) to assess temporal changes in malaria notifications in the study sites. Then, we conducted a space-time cluster analysis to investigate the potential of malaria spread from the study sites (sources) to elsewhere (sinks). Finally, we present the sociodemographic characteristics of exported cases over time using multivariate logistic regressions. Our results show that there was no upsurge in malaria cases in the study sites and exported cases did not trigger outbreaks in other localities. Exported malaria infections originating from PVH and ATM were typically found in working age literate males involved in mining, farming or traveling. We suggest that efficient control measures, such as ensuring timely diagnosis and treatment; fostering integrated vector control; promoting health education; and prevention, detection and containment of outbreaks, if properly implemented and sustained, may prevent local and introduced malaria outbreaks during and after hydropower dam construction in the Amazon.

Relative contribution of low-density and asymptomatic infections to Plasmodium vivax transmission in the Amazon: pooled analysis of individual participant data from population-based cross-sectional surveys.

Background: Low-density and asymptomatic Plasmodium vivax infections remain largely undetected and untreated and may contribute significantly to malaria transmission in the Amazon. Methods: 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. Findings: 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. Interpretation: 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. Funding: US National Institutes of Health, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Belgium Development Cooperation.

Cohort profile: the Mâncio Lima cohort study of urban malaria in Amazonian Brazil.

PURPOSE: This population-based open cohort study aims to investigate biological and sociodemographic drivers of malaria transmission in the main urban hotspot of Amazonian Brazil. PARTICIPANTS: Nearly 20% of the households in the northwestern town of Mâncio Lima were randomly selected and 2690 participants were enrolled since April 2018. Sociodemographic, housing quality, occupational, behavioural and morbidity information and travel histories were collected during consecutive study visits. Blood samples from participants>3 months old were used for malaria diagnosis and human genetic studies; samples from participants with laboratory-confirmed malaria have been cryopreserved for genetic and phenotypic characterisation of parasites. Serology was introduced in 2020 to measure the prevalence and longevity of SARS-CoV-2 IgG antibodies. FINDINGS TO DATE: Malaria prevalence rates were low (up to 1.0% for Plasmodium vivax and 0.6% for P. falciparum) during five consecutive cross-sectional surveys between April-May 2018 and October-November 2020; 63% of infections diagnosed by microscopy were asymptomatic. Malaria risk is heterogeneously distributed, with 20% study participants contributing 86% of the overall burden of P. vivax infection. Adult males are at greatest risk of infection and human mobility across the urban-rural interface may contribute to sustained malaria transmission. Local P. vivax parasites are genetically diverse and fragmented into discrete inbred lineages that remain stable across space and time. FUTURE PLANS: Two follow-up visits, with similar study protocols, are planned in 2021. We aim to identify high-risk individuals that fuel onwards malaria transmission and represent a priority target for more intensive and effective control interventions. TRIAL REGISTRATION NUMBER: NCT03689036.

Low-level Plasmodium vivax exposure, maternal antibodies, and anemia in early childhood: Population-based birth cohort study in Amazonian Brazil.

BACKGROUND: Malaria causes significant morbidity and mortality in children under 5 years of age in sub-Saharan Africa and the Asia-Pacific region. Neonates and young infants remain relatively protected from clinical disease and the transplacental transfer of maternal antibodies is hypothesized as one of the protective factors. The adverse health effects of Plasmodium vivax malaria in early childhood-traditionally viewed as a benign infection-remain largely neglected in relatively low-endemicity settings across the Amazon. METHODOLOGY/PRINCIPAL FINDINGS: Overall, 1,539 children participating in a birth cohort study in the main transmission hotspot of Amazonian Brazil had a questionnaire administered, and blood sampled at the two-year follow-up visit. Only 7.1% of them experienced malaria confirmed by microscopy during their first 2 years of life- 89.1% of the infections were caused by P. vivax. Young infants appear to be little exposed to, or largely protected from infection, but children >12 months of age become as vulnerable to vivax malaria as their mothers. Few (1.4%) children experienced ≥4 infections during the 2-year follow-up, accounting for 43.4% of the overall malaria burden among study participants. Antenatal malaria diagnosed by microscopy during pregnancy or by PCR at delivery emerged as a significant correlate of subsequent risk of P. vivax infection in the offspring (incidence rate ratio, 2.58; P = 0.002), after adjusting for local transmission intensity. Anti-P. vivax antibodies measured at delivery do not protect mothers from subsequent malaria; whether maternal antibodies transferred to the fetus reduce early malaria risk in children remains undetermined. Finally, recent and repeated vivax malaria episodes in early childhood are associated with increased risk of anemia at the age of 2 years in this relatively low-endemicity setting. CONCLUSIONS/SIGNIFICANCE: Antenatal infection increases the risk of vivax malaria in the offspring and repeated childhood P. vivax infections are associated with anemia at the age of 2 years.

Interacting Epidemics in Amazonian Brazil: Prior Dengue Infection Associated With Increased Coronavirus Disease 2019 (COVID-19) Risk in a Population-Based Cohort Study.

BACKGROUND: Immunity after dengue virus (DENV) infection has been suggested to cross-protect from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mortality. METHODS: We tested whether serologically proven prior DENV infection diagnosed in September-October 2019, before the coronavirus disease 2019 (COVID-19) pandemic, reduced the risk of SARS-CoV-2 infection and clinically apparent COVID-19 over the next 13 months in a population-based cohort in Amazonian Brazil. Mixed-effects multiple logistic regression analysis was used to identify predictors of infection and disease, adjusting for potential individual and household-level confounders. Virus genomes from 14 local SARS-CoV-2 isolates were obtained using whole-genome sequencing. RESULTS: Anti-DENV immunoglobulin G (IgG) was found in 37.0% of 1285 cohort participants (95% confidence interval [CI]: 34.3% to 39.7%) in 2019, with 10.4 (95% CI: 6.7-15.5) seroconversion events per 100 person-years during the follow-up. In 2020, 35.2% of the participants (95% CI: 32.6% to 37.8%) had anti-SARS-CoV-2 IgG and 57.1% of the 448 SARS-CoV-2 seropositives (95% CI: 52.4% to 61.8%) reported clinical manifestations at the time of infection. Participants aged >60 years were twice more likely to have symptomatic COVID-19 than children under 5 years. Locally circulating SARS-CoV-2 isolates were assigned to the B.1.1.33 lineage. Contrary to the cross-protection hypothesis, prior DENV infection was associated with twice the risk of clinically apparent COVID-19 upon SARS-CoV-2 infection, with P values between .025 and .039 after adjustment for identified confounders. CONCLUSIONS: Higher risk of clinically apparent COVID-19 among individuals with prior dengue has important public health implications for communities sequentially exposed to DENV and SARS-CoV-2 epidemics.

Monitoring Plasmodium vivax resistance to antimalarials: Persisting challenges and future directions.

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.

Human mobility and urban malaria risk in the main transmission hotspot of Amazonian Brazil.

Malaria in the Amazon is often perceived as an exclusively rural disease, but transmission has been increasingly documented within and near urban centers. Here we explore patterns and causes of urban-to-rural mobility, which places travelers at risk of malaria in Mâncio Lima, the main malaria hotspot in northwestern Brazil. We also analyze rural-to-urban mobility caused by malaria treatment seeking, which poses an additional risk of infection to urban residents. We show that the rural localities most frequently visited by urban residents-typically farming settlements in the vicinity of the town-are those with the most intense malaria transmission and also the most frequent source localities of imported malaria cases diagnosed in the town. The most mobile urban residents are typically poor males 16 to 60-years old from multi-sited households who lack a formal job. Highly mobile residents represent a priority target for more intensive and effective malaria control interventions, that cannot be readily delivered to the entire community, in this and similar urbanized endemic settings across the Amazon.