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      High Rates of Asymptomatic, Sub-microscopic Plasmodium vivax Infection and Disappearing Plasmodium falciparum Malaria in an Area of Low Transmission in Solomon Islands

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          Abstract

          Introduction

          Solomon Islands is intensifying national efforts to achieve malaria elimination. A long history of indoor spraying with residual insecticides, combined recently with distribution of long lasting insecticidal nets and artemether-lumefantrine therapy, has been implemented in Solomon Islands. The impact of these interventions on local endemicity of Plasmodium spp. is unknown.

          Methods

          In 2012, a cross-sectional survey of 3501 residents of all ages was conducted in Ngella, Central Islands Province, Solomon Islands. Prevalence of Plasmodium falciparum, P. vivax, P. ovale and P. malariae was assessed by quantitative PCR (qPCR) and light microscopy (LM). Presence of gametocytes was determined by reverse transcription quantitative PCR (RT-qPCR).

          Results

          By qPCR, 468 Plasmodium spp. infections were detected (prevalence = 13.4%; 463 P. vivax, five mixed P. falciparum/P. vivax, no P. ovale or P. malariae) versus 130 by LM (prevalence = 3.7%; 126 P. vivax, three P. falciparum and one P. falciparum/P. vivax). The prevalence of P. vivax infection varied significantly among villages (range 3.0–38.5%, p<0.001) and across age groups (5.3–25.9%, p<0.001). Of 468 P. vivax infections, 72.9% were sub-microscopic, 84.5% afebrile and 60.0% were both sub-microscopic and afebrile. Local residency, low education level of the household head and living in a household with at least one other P. vivax infected individual increased the risk of P. vivax infection. Overall, 23.5% of P. vivax infections had concurrent gametocytaemia. Of all P. vivax positive samples, 29.2% were polyclonal by MS16 and msp1F3 genotyping. All five P. falciparum infections were detected in residents of the same village, carried the same msp2 allele and four were positive for P. falciparum gametocytes.

          Conclusion

          P. vivax infection remains endemic in Ngella, with the majority of cases afebrile and below the detection limit of LM. P. falciparum has nearly disappeared, but the risk of re-introductions and outbreaks due to travel to nearby islands with higher malaria endemicity remains.

          Author Summary

          Solomon Islands, an island nation in the Southwest Pacific that has seen dramatic reductions in malaria transmission over the past 20 years, is aiming for malaria elimination. There is an increasing recognition that a substantial reservoir of asymptomatic and often sub-microscopic Plasmodium spp. infections exists even in low transmission settings. However, the potential role for these infections in sustaining transmission and the difference in response of the two most common malaria parasites, P. vivax and P. falciparum, to intensified control remains unclear. In May-June 2012, we therefore performed a cross-sectional survey of 3501 residents of all ages of Ngella, a low transmission area in Central Islands Province, to assess the prevalence of P. vivax and P. falciparum infection, determine the proportion of sub-microscopic and afebrile infections and evaluate whether gametocytaemic, and thus potentially infectious, individuals are present. Our survey showed a marked epidemiological contrast between P. vivax and P. falciparum. Although prevalence varied significantly among different regions of Ngella, P. vivax remains firmly endemic, with high rates of sub-microscopic, afebrile and genetically diverse infections. The presence of gametocytes among both sub-microscopic and microscopy positive, asymptomatic infections indicates that these infections contribute significantly to sustaining P. vivax transmission. P. falciparum, on the other hand, appears to be more amenable to control interventions. Only five P. falciparum infected individuals were detected, and all were residents of the same village. These infections carried the same msp2 clone. This difference highlights the larger challenge of eliminating P. vivax compared to P. falciparum in areas where they are co-endemic. In particular, the challenge posed by the presence of a large reservoir of silent P. vivax infections will need to be addressed if control of this parasite is to be accelerated and elimination achieved.

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          Most cited references43

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          Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination.

          Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.
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            Malaria in Brazil: an overview

            Malaria is still a major public health problem in Brazil, with approximately 306 000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in Brazilian populations have also been providing important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates. The present difficulties in reducing economic and social risk factors that determine the incidence of malaria in the Amazon Region render impracticable its elimination in the region. As a result, a malaria-integrated control effort - as a joint action on the part of the government and the population - directed towards the elimination or reduction of the risks of death or illness, is the direction adopted by the Brazilian government in the fight against the disease.
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              Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection.

              Submicroscopic Plasmodium falciparum gametocytemia (<5,000 gametocytes/mL) is common and may result in mosquito infection. We assessed the relation between gametocyte density and mosquito infection under experimental and field conditions using real-time quantitative nucleic acid sequence-based amplification (QT-NASBA) for gametocyte quantification. Serial dilutions of NF54 P. falciparum gametocytes showed a positive association between gametocyte density and the proportion of infected mosquitoes (beta=6.1; 95% confidence interval [CI], 2.7-9.6; P=0.001). Successful infection became unlikely below an estimated density of 250-300 gametocytes/mL. In the field, blood samples of 100 naturally infected children showed a positive association between gametocyte density and oocyst counts in mosquitoes (beta=0.38; 95% CI, 0.14-0.61; P=0.002). The relative contribution to malaria transmission was similar for carriers with submicroscopic and microscopic gametocytemia. Our results show that transmission occurs efficiently at submicroscopic gametocyte densities and that carriers harboring submicroscopic gametocytemia constitute a considerable proportion of the human infectious reservoir.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                21 May 2015
                May 2015
                : 9
                : 5
                : e0003758
                Affiliations
                [1 ]The Walter & Eliza Hall Institute, Melbourne, Australia
                [2 ]University of Melbourne, Melbourne, Australia
                [3 ]National Health Training and Research Institute, Ministry of Health, Honiara, Solomon Islands
                [4 ]Australian Army Malaria Institute, Brisbane, Australia
                [5 ]National Vector Borne Disease Control Program, Ministry of Health, Honiara, Solomon Islands
                [6 ]School of Population Health, University of Queensland, Brisbane, Australia
                [7 ]Case Western Reserve University, Cleveland, Ohio, United States of America
                [8 ]Barcelona Centre for International Health Research (CRESIB), Barcelona, Spain
                University of Sao Paulo, BRAZIL
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AWD GDS MW JWK IM. Performed the experiments: AW AWD CK IH JL VV DP. Analyzed the data: AW CK AEB IM. Contributed reagents/materials/analysis tools: AEB. Wrote the paper: AW CK GDS AEB MW JWK IM.

                Article
                PNTD-D-14-02036
                10.1371/journal.pntd.0003758
                4440702
                25996619
                705507f8-1a7e-4597-ad81-b4abeaabd724
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 20 November 2014
                : 13 April 2015
                Page count
                Figures: 3, Tables: 2, Pages: 18
                Funding
                This work was supported by the TransEPI consortium funded by the Bill & Melinda Gates, the National health and Medical Research Council of Australia (NHMRC, #1021544) and the Southwest Pacific International Centre of Excellence in Malaria Research (NIH grant U19AI089686 “Research to control and eliminate malaria in the Southwest Pacific”). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. IM is supported by an NHMRC Senior Research Fellowship (#1043345) and AW is supported by an NHMRC Postgraduate Scholarship (#APP1056511). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                The data are available on the DRYAD digital repository. doi: 10.5061/dryad.545tv.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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