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      The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis

      research-article
      1 , 2 , , 3 , 1 , 4 , 5 , 1 , 3 , 6 , 7 , 8 , 9 , 10 , 1 , 8 , 11 , 12 , 13 , 4 , 14 , 1 , 15 , 16 , 17 , 4 , 18 , 19 , 20 , 21 , 22 , 17 , 23 , 24 , 1 , 15 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 33 , 34 , 35 , 1 , 36 , 31 , 32 , 37 , 38 , 39 , 40 , 5 , 34 , 41 , 42 , 18 , 43 , 31 , 44 , 45 , 4 , 18 , 4 , 12 , 4 , 46 , 40 , 4 , 46 , 47 , 48 , 4 , 12 , 15 , 49 , 12 , 4 , 5 , 4 , 18 , 4 , 12 , 1 , 2 , 4 , 12 ,
      BMC Medicine
      BioMed Central
      Plasmodium vivax, Chloroquine, Primaquine, Haemoglobin, Pooled analysis, Haemolysis

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          Abstract

          Background

          Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax.

          Methods

          A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model.

          Results

          In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was − 0.13 g/dL [− 0.27, 0.01] lower at day of nadir ( p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 ( p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration − 0.72 g/dL [− 0.90, − 0.54] lower than patients without recurrence ( p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL.

          Conclusions

          Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals.

          Trial registration

          This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

          Electronic supplementary material

          The online version of this article (10.1186/s12916-019-1386-6) contains supplementary material, which is available to authorized users.

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          Most cited references41

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          Vivax malaria: neglected and not benign.

          Plasmodium vivax threatens almost 40% of the world's population, resulting in 132-391 million clinical infections each year. Most of these cases originate from Southeast Asia and the Western Pacific, although a significant number also occurs in Africa and South America. Although often regarded as causing a benign and self-limiting infection, there is increasing evidence that the overall burden, economic impact, and severity of disease from P. vivax have been underestimated. Malaria control strategies have had limited success and are confounded by the lack of access to reliable diagnosis, emergence of multidrug resistant isolates, the parasite's ability to transmit early in the course of disease and relapse from dormant liver stages at varying time intervals after the initial infection. Progress in reducing the burden of disease will require improved access to reliable diagnosis and effective treatment of both blood-stage and latent parasites, and more detailed characterization of the epidemiology, morbidity, and economic impact of vivax malaria. Without these, vivax malaria will continue to be neglected by ministries of health, policy makers, researchers, and funding bodies.
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            Geographical variation in Plasmodium vivax relapse

            Background Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission. Methods A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse. Results Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas. Conclusions The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations.
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              A prospective comparative study of knowlesi, falciparum, and vivax malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium vivax but no mortality with early referral and artesunate therapy.

              Plasmodium knowlesi commonly causes severe malaria in Malaysian Borneo, with high case-fatality rates reported. We compared risk, spectrum, and outcome of severe disease from P. knowlesi, Plasmodium falciparum, and Plasmodium vivax and outcomes following introduction of protocols for early referral and intravenous artesunate for all severe malaria. From September 2010 to October 2011 we prospectively assessed nonpregnant patients aged ≥12 years admitted to Queen Elizabeth Hospital (QEH), Sabah, with polymerase chain reaction-confirmed Plasmodium monoinfection. Standardized referral and prereferral intravenous artesunate were instituted at district hospitals. Severe malaria occurred in 38 of 130 (29%) patients with P. knowlesi, 13 of 122 (11%) with P. falciparum, and 7 of 43 (16%) with P. vivax. The commonest severity criteria in knowlesi malaria included parasitemia >100 000/µL (n = 18), jaundice (n = 20), respiratory distress (n = 14), hypotension (n = 13), and acute kidney injury (n = 9). On multivariate analysis, P. knowlesi was associated with a 2.96-fold (95% confidence interval, 1.19-7.38-fold) greater risk of severity than P. falciparum (P = .020); only parasitemia and schizontemia >10% independently predicted knowlesi severity. Risk of severe knowlesi malaria increased 11-fold with parasitemia >20 000/µL, and 28-fold with parasitemia >100 000/µL. Nearly all (92%) knowlesi malaria patients received oral artemisinin therapy; 36 of 38 (95%) and 39 of 92 (42%) with severe and nonsevere disease, respectively, also received ≥1 dose of intravenous artesunate. No deaths occurred from any species. Plasmodium knowlesi is the commonest cause of severe malaria at QEH, with parasitemia the major risk factor for severity. Early referral and treatment with artesunate was highly effective for severe malaria from all species and associated with zero mortality.
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                Author and article information

                Contributors
                rob.commons@wwarn.org
                +618 8946 8600 , ric.price@wwarn.org
                Journal
                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central (London )
                1741-7015
                1 August 2019
                1 August 2019
                2019
                : 17
                : 151
                Affiliations
                [1 ]ISNI 0000 0000 8523 7955, GRID grid.271089.5, Global Health Division, , Menzies School of Health Research and Charles Darwin University, ; Darwin, Northern Territory Australia
                [2 ]WorldWide Antimalarial Resistance Network (WWARN), Clinical Module, Darwin, Northern Territory Australia
                [3 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, , The University of Melbourne, ; Melbourne, Victoria Australia
                [4 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, , University of Oxford, ; Oxford, UK
                [5 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, , Mahidol University, ; Mae Sot, Thailand
                [6 ]ICAP, Columbia University Mailman School of Public Health, Addis Ababa, Ethiopia
                [7 ]ISNI 0000 0001 1250 5688, GRID grid.7123.7, Addis Ababa University, ; Addis Ababa, Ethiopia
                [8 ]ISNI 0000 0000 4319 4715, GRID grid.418720.8, Armauer Hansen Research Institute, ; Addis Ababa, Ethiopia
                [9 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Departamento de Salud Pública, , Universidad de Barcelona, ; Barcelona, Spain
                [10 ]Organización Panamericana de Salud, Oficina de País Bolivia, La Paz, Bolivia
                [11 ]GRID grid.452387.f, Malaria and Neglected Tropical Diseases Research Team, Bacterial, Parasitic, Zoonotic Diseases Research Directorate, , Ethiopian Public Health Institute, ; Addis Ababa, Ethiopia
                [12 ]ISNI 0000 0004 1937 0490, GRID grid.10223.32, Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, , Mahidol University, ; Bangkok, Thailand
                [13 ]GRID grid.440467.5, Nangarhar Medical Faculty, , Nangarhar University, ; Jalalabad, Afghanistan
                [14 ]ISNI 0000 0004 1795 0993, GRID grid.418754.b, Eijkman-Oxford Clinical Research Unit, ; Jakarta, Indonesia
                [15 ]Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah Malaysia
                [16 ]ISNI 0000 0004 0432 5267, GRID grid.452605.0, Medicines for Malaria Venture, ; Geneva, Switzerland
                [17 ]ISNI 0000 0004 0606 294X, GRID grid.415063.5, Medical Research Council Unit The Gambia at LSTMH, ; Fajara, The Gambia
                [18 ]WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK
                [19 ]ISNI 0000 0001 0723 0931, GRID grid.418068.3, Institute of Drug Technology (Farmanguinhos), , Oswaldo Cruz Foundation (FIOCRUZ), ; Rio de Janeiro, Brazil
                [20 ]ISNI 0000 0001 0723 0931, GRID grid.418068.3, Vice-presidency of Research and Reference Laboratories, , Oswaldo Cruz Foundation (FIOCRUZ), ; Rio de Janeiro, Brazil
                [21 ]ISNI 0000 0004 1936 9764, GRID grid.48004.38, Liverpool School of Tropical Medicine, ; Liverpool, UK
                [22 ]Department of Internal Medicine, Tergooi Hospital, Hilversum, the Netherlands
                [23 ]Superintendência de Vigilância em Saúde do Estado do Amapá - SVS/AP, Macapá, Amapá Brazil
                [24 ]ISNI 0000 0004 0643 9014, GRID grid.440559.9, Universidade Federal do Amapá – UNIFAP, ; Macapá, Amapá Brazil
                [25 ]ISNI 0000 0001 2163 0069, GRID grid.416738.f, U.S. President’s Malaria Initiative, Malaria Branch, U.S. Centers for Disease Control and Prevention, ; Atlanta, USA
                [26 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Global Health Group, , University of California San Francisco, ; San Francisco, USA
                [27 ]ISNI 0000000404654431, GRID grid.5650.6, Centre for Infection and Immunity Amsterdam (CINEMA), Division of Infectious Diseases, Tropical Medicine and AIDS, , Academic Medical Centre, ; Amsterdam, the Netherlands
                [28 ]ISNI 0000 0001 1250 5688, GRID grid.7123.7, Department of Biology, , Addis Ababa University, ; Addis Ababa, Ethiopia
                [29 ]ISNI 0000 0001 2034 9160, GRID grid.411903.e, Department of Biology, , Jimma University, ; Jimma, Ethiopia
                [30 ]International Centre for Diarrheal Diseases and Research, Dhaka, Bangladesh
                [31 ]ISNI 0000 0004 0486 0972, GRID grid.418153.a, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, ; Manaus, Brazil
                [32 ]ISNI 0000 0000 8024 0602, GRID grid.412290.c, Universidade do Estado do Amazonas, ; Manaus, Brazil
                [33 ]Fundação Oswaldo Cruz, Instituto Leônidas e Maria Deane (FIOCRUZ-Amazonas), Manaus, Brazil
                [34 ]ISNI 0000 0004 0425 469X, GRID grid.8991.9, Department of Infectious and Tropical Diseases, , London School of Hygiene and Tropical Medicine, ; London, UK
                [35 ]HealthNet-TPO, Kabul, Afghanistan
                [36 ]The Department of Pharmacology and Therapy, Faculty of Medicine, Nusa Cendana University, Kupang, Indonesia
                [37 ]Centro de Pesquisa em Medicina Tropical de Rondônia (CEPEM), Porto Velho, Rondônia Brazil
                [38 ]GRID grid.440563.0, Universidade Federal de Rondônia (UNIR), ; Porto Velho, Rondônia Brazil
                [39 ]ISNI 0000000404654431, GRID grid.5650.6, Division of Infectious Diseases, Tropical Medicine and AIDS, , Academic Medical Center, ; Amsterdam, the Netherlands
                [40 ]ISNI 0000 0004 0620 1102, GRID grid.414275.1, Tropical Diseases Clinical Research Center, , Cho Ray Hospital, ; Ho Chi Minh City, Vietnam
                [41 ]ISNI 0000 0001 0571 5193, GRID grid.411639.8, Department of Medicine, Kasturba Medical College, , Manipal Academy of Higher Education, ; Madhav Nagar, Manipal, Karnataka India
                [42 ]ISNI 0000 0001 0571 5193, GRID grid.411639.8, Manipal McGill Center for Infectious Diseases, , Manipal Academy of Higher Education, ; Manipal, Karnataka India
                [43 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Genome Sciences, , University of Washington, ; Seattle, USA
                [44 ]ISNI 0000 0000 8024 0602, GRID grid.412290.c, Programa de Pós-graduação em Medicina Tropical, , Universidade do Estado do Amazonas, ; Manaus, Brazil
                [45 ]ISNI 0000 0001 0723 0931, GRID grid.418068.3, Instituto Nacional de Infectologia Evandro Chagas, , Fundação Oswaldo Cruz, ; Rio de Janeiro, Brazil
                [46 ]ISNI 0000 0004 0429 6814, GRID grid.412433.3, Oxford University Clinical Research Unit, ; Ho Chi Minh City, Vietnam
                [47 ]ISNI 0000 0001 2171 5249, GRID grid.271300.7, Federal University of Pará (Universidade Federal do Pará - UFPA), ; Belém, Pará Brazil
                [48 ]GRID grid.490687.4, Public Health Laboratory, Department of Public Health, , Ministry of Health, ; Thimphu, Bhutan
                [49 ]Gleneagles Hospital, Kota Kinabalu, Sabah Malaysia
                Author information
                http://orcid.org/0000-0002-3359-5632
                Article
                1386
                10.1186/s12916-019-1386-6
                6670141
                31366382
                37e39440-9df6-45ea-b2fb-413f0889a8a5
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 10 March 2019
                : 9 July 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Award ID: 1104975
                Award ID: 1135820
                Award ID: 1138860
                Award ID: 1134989
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001232, Royal Australasian College of Physicians;
                Funded by: FundRef http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: OPP1164105 and OPP1054404
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 200909
                Award Recipient :
                Funded by: Asia Pacific Malaria Elimination Network
                Award ID: None
                Award Recipient :
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico (BR)
                Funded by: Tropical Network Fund, Nuffield Department of Clinical Medicine, University of Oxford
                Award ID: None
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004371, Exxon Mobil Corporation;
                Award ID: None
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Medicine
                plasmodium vivax,chloroquine,primaquine,haemoglobin,pooled analysis,haemolysis
                Medicine
                plasmodium vivax, chloroquine, primaquine, haemoglobin, pooled analysis, haemolysis

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