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      Performance of a High-Sensitivity Rapid Diagnostic Test for Plasmodium falciparum Malaria in Asymptomatic Individuals from Uganda and Myanmar and Naive Human Challenge Infections

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          Abstract.

          Sensitive field-deployable diagnostic tests can assist malaria programs in achieving elimination. The performance of a new Alere™ Malaria Ag P.f Ultra Sensitive rapid diagnostic test (uRDT) was compared with the currently available SD Bioline Malaria Ag P.f RDT in blood specimens from asymptomatic individuals in Nagongera, Uganda, and in a Karen Village, Myanmar, representative of high- and low-transmission areas, respectively, as well as in pretreatment specimens from study participants from four Plasmodium falciparum-induced blood-stage malaria (IBSM) studies. A quantitative reverse transcription PCR (qRT-PCR) and a highly sensitive enzyme-linked immunosorbent assay (ELISA) test for histidine-rich protein II (HRP2) were used as reference assays. The uRDT showed a greater than 10-fold lower limit of detection for HRP2 compared with the RDT. The sensitivity of the uRDT was 84% and 44% against qRT-PCR in Uganda and Myanmar, respectively, and that of the RDT was 62% and 0% for the same two sites. The specificities of the uRDT were 92% and 99.8% against qRT-PCR for Uganda and Myanmar, respectively, and 99% and 99.8% against the HRP2 reference ELISA. The RDT had specificities of 95% and 100% against qRT-PCR for Uganda and Myanmar, respectively, and 96% and 100% against the HRP2 reference ELISA. The uRDT detected new infections in IBSM study participants 1.5 days sooner than the RDT. The uRDT has the same workflow as currently available RDTs, but improved performance characteristics to identify asymptomatic malaria infections. The uRDT may be a useful tool for malaria elimination strategies.

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          A large proportion of asymptomatic Plasmodium infections with low and sub-microscopic parasite densities in the low transmission setting of Temotu Province, Solomon Islands: challenges for malaria diagnostics in an elimination setting

          Background Many countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting. Methods During the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared. Results A total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections. Conclusion Asymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.
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            Asymptomatic carriers of Plasmodium spp. as infection source for malaria vector mosquitoes in the Brazilian Amazon.

            We have described the existence of asymptomatic carriers of Plasmodium vivax and Plasmodium falciparum infections in native Amazon populations. Most of them had low parasitemias, detected only by polymerase chain reaction (PCR). Because they remain symptomless and untreated, we wanted to determine whether they could infect Anopheles darlingi Root, the main Brazilian vector, and act as disease reservoirs. Fifteen adult asymptomatic patients (PCR positive only) were selected, and experimental infections of mosquitoes were performed by direct feeding and by a membrane-feeding system. Seventeen adult symptomatic patients with high parasitemias were used as controls. We found an infection rate in An. darlingi of 1.2% for the asymptomatic carriers and 22% for the symptomatic carriers. Although the asymptomatic group infected mosquitoes at a much lower rate, these patients remain infective longer than treated, symptomatic patients. Also, the prevalence of asymptomatic infections is 4 to 5 times higher than symptomatic infections among natives. These results have implications for the malaria control program in Brazil, which focuses essentially on the treatment of symptomatic patients.
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              Malaria transmission, infection, and disease at three sites with varied transmission intensity in Uganda: implications for malaria control.

              The intensification of control interventions has led to marked reductions in malaria burden in some settings, but not others. To provide a comprehensive description of malaria epidemiology in Uganda, we conducted surveillance studies over 24 months in 100 houses randomly selected from each of three subcounties: Walukuba (peri-urban), Kihihi (rural), and Nagongera (rural). Annual entomological inoculation rate (aEIR) was estimated from monthly Centers for Disease Control and Prevention (CDC) light trap mosquito collections. Children aged 0.5-10 years were provided long-lasting insecticidal nets (LLINs) and followed for measures of parasite prevalence, anemia and malaria incidence. Estimates of aEIR were 2.8, 32.0, and 310 infectious bites per year, and estimates of parasite prevalence 7.4%, 9.3%, and 28.7% for Walukuba, Kihihi, and Nagongera, respectively. Over the 2-year study, malaria incidence per person-years decreased in Walukuba (0.51 versus 0.31, P = 0.001) and increased in Kihihi (0.97 versus 1.93, P < 0.001) and Nagongera (2.33 versus 3.30, P < 0.001). Of 2,582 episodes of malaria, only 8 (0.3%) met criteria for severe disease. The prevalence of anemia was low and not associated with transmission intensity. In our cohorts, where LLINs and prompt effective treatment were provided, the risk of complicated malaria and anemia was extremely low. However, malaria incidence was high and increased over time at the two rural sites, suggesting improved community-wide coverage of LLIN and additional malaria control interventions are needed in Uganda.
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                Author and article information

                Journal
                Am J Trop Med Hyg
                Am. J. Trop. Med. Hyg
                tpmd
                tropmed
                The American Journal of Tropical Medicine and Hygiene
                The American Society of Tropical Medicine and Hygiene
                0002-9637
                1476-1645
                08 November 2017
                07 August 2017
                07 August 2017
                : 97
                : 5
                : 1540-1550
                Affiliations
                [1 ]Diagnostics Program, PATH, Seattle, Washington;
                [2 ]Infectious Disease Research Collaboration, Kampala, Uganda;
                [3 ]University of California San Francisco, San Francisco, California;
                [4 ]Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand;
                [5 ]Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand;
                [6 ]QIMR Berghofer Medical Research Institute, Brisbane, Australia;
                [7 ]Department of Laboratory Medicine, University of Washington, Seattle, Washington;
                [8 ]Department of Microbiology, University of Washington, Seattle, Washington;
                [9 ]Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington;
                [10 ]Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom;
                [11 ]Bill & Melinda Gates Foundation, Seattle, Washington
                Author notes
                [* ]Address correspondence to Gonzalo J. Domingo, Diagnostics Program, PATH, Seattle, Washington 98109. E-mail: gdomingo@ 123456path.org

                Financial support: This work was funded by the Bill & Melinda Gates Foundation, grant number OPP1135840.

                Authors’ addresses: Smita Das, Ihn Kyung Yang, Becky Barney, Roger Peck, Tomoka Nakamura, Michael Kalnoky, Paul Labarre, and Gonzalo J. Domingo, Diagnostics Program, PATH, Seattle, WA, E-mails: sdas@ 123456path.org , ikjang@ 123456path.org , rbarney@ 123456path.org , rpeck@ 123456path.org , tomoka.nakamura09@ 123456gmail.com , mkalnoky@ 123456path.org , plabarre@ 123456unicef.org , and gdomingo@ 123456path.org . John C. Rek and Emmanuel Arinaitwe, Infectious Disease Research Collaboration, Mulago Hospital Complex, Kampala, Uganda, E-mails: jrek@ 123456idrc-uganda.org and earinaitwe@ 123456idrc-uganda.org . Harriet Adrama, Epicentre, Uganda Research Base, Mbarara, Uganda, E-mail: harriet.adrama@ 123456gmail.com . Maxwell Murphy, Division of Infectious Diseases, University of California, San Francisco, CA, E-mail: maxwell.murphy@ 123456ucsf.edu . Mallika Imwong, Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand, E-mail: mallika.imw@ 123456mahidol.ac.th . Clare L. Ling, Warat Haohankhunnatham, and Francois Nosten, Microbiology Department, Shoklo Malaria Research Unit, Mae Sot, Thailand, E-mails: clare@ 123456tropmedres.ac , warat@ 123456shoklo-unit.com , and francois@ 123456tropmedres.ac . Stephane Proux, Department of Parasitology, Shoklo Malaria Research Unit, Mae Sot, Thailand, E-mail: steph@ 123456shoklo-unit.com . Melissa Rist and James S. McCarthy, Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Brisbane, Australia, E-mails: melissa.rist@ 123456qimrberghofer.edu.au and j.mccarthy@ 123456uq.edu.au . Annette M. Seilie, Amelia Hanron, Glenda Daza, Ming Chang, and Sean C. Murphy, Department of Laboratory Medicine, University of Washington, Seattle, WA, E-mails: amseilie@ 123456uw.edu , ahanron@ 123456uw.edu , gdaza@ 123456uw.edu , minchang@ 123456uw.edu , and murphysc@ 123456uw.edu . Bryan Greenhouse, Department of Medicine, UCSF School of Medicine, San Francisco, CA, E-mail: bryan.greenhouse@ 123456ucsf.edu . Sophie Allauzen, Bill & Melinda Gates Foundation, Global Health Diagnostics, Seattle, WA, E-mail: sophie.allauzen@ 123456gatesfoundation.org .

                Article
                tpmd170245
                10.4269/ajtmh.17-0245
                5817764
                28820709
                f554e462-4966-4578-a028-8704a39ad657
                © The American Society of Tropical Medicine and Hygiene

                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
                : 25 March 2017
                : 24 May 2017
                Page count
                Pages: 11
                Categories
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                Infectious disease & Microbiology
                Infectious disease & Microbiology

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