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.

We examined the mitogenomes of a large global collection of human malaria parasites to explore how and when Plasmodium falciparum and P. vivax entered the Americas. We found evidence of a significant contribution of African and South Asian lineages to present-day New World malaria parasites with additional P. vivax lineages appearing to originate from Melanesia that were putatively carried by the Australasian peoples who contributed genes to Native Americans. Importantly, mitochondrial lineages of the P. vivax-like species P. simium are shared by platyrrhine monkeys and humans in the Atlantic Forest ecosystem, but not across the Amazon, which most likely resulted from one or a few recent human-to-monkey transfers. While enslaved Africans were likely the main carriers of P. falciparum mitochondrial lineages into the Americas after the conquest, additional parasites carried by Australasian peoples in pre-Columbian times may have contributed to the extensive diversity of extant local populations of P. vivax.

Five community-based cross-sectional surveys of malaria morbidity and associated risk factors in remote riverine populations in northwestern Brazil showed average parasite rates of 4.2% (thick-smear microscopy) and 14.4% (polymerase chain reaction [PCR]) in the overall population, with a spleen rate of 13.9% among children 2–9 years of age. Plasmodium vivax was 2.8 times more prevalent than P. falciparum, with rare instances of P. malariae and mixed-species infections confirmed by PCR; 9.6% of asymptomatic subjects had parasitemias detected by PCR. Low-grade parasitemia detected by PCR only was a risk factor for anemia, after controlling for age and other covariates. Although clinical and subclinical infections occurred in all age groups, the risk of infection and disease decreased significantly with increasing age, after adjustment for several covariates in multilevel logistic regression models. These findings suggest that the continuous exposure to hypo- or mesoendemic malaria may induce significant anti-parasite and anti-disease immunity in native Amazonians.

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 center dot 8% and 2 center dot 1% of them by PCR and microscopy, respectively. 58 center dot 5% to 92.6% of P vivax infections were asymptomatic and 61 center dot 2% to 96 center dot 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 center dot 7% to 24 center dot 9% of the community-wide P vivax transmission, while asymptomatic carriers are the source of 28 center dot 2% to 79 center dot 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. Copyright (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus, but not in the main malaria hotspots across the Amazon Basin of Brazil, where CQ is routinely co-administered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (Arm 1) or concomitant (Arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in Arm 1 subjects, who had PQ administered only at the end of the 28-day follow up. We found adequate clinical and parasitological responses in all subjects assigned to Arm 2. However, 2.2% of Arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in Arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo. In contrast, ex-vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ co-administration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g. CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax-infected populations.