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VARIABILITY IN WHITE BLOOD CELL COUNT DURING UNCOMPLICATED MALARIA AND IMPLICATIONS FOR PARASITE DENSITY ESTIMATION: A WORLDWIDE ANTIMALARIAL RESISTANCE NETWORK INDIVIDUAL PATIENT DATA META-ANALYSIS
Andre Daher - Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos (Farmanguinhos). Rio de Janeiro, RJ, Brazil / Fundação Oswaldo Cruz. Presidência. Vice-presidência de Laboratórios de Pesquisa e Referência. Rio de Janeiro, RJ, Brazil / Liverpool School of Tropical Medicine. Liverpool, UK.
Marcus Lacerda - Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brazil / Fundação Oswaldo Cruz. Instituto Leônidas & Maria Deane. Manaus, AM, Brasil.
Members of WWARN White Blood Cell Count in Malaria Study Group: Elke Wynberg, Department of Infectious Diseases, Public Health Service of Amsterdam, Amsterdam, the Netherlands; Robert J Commons, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia and General and Subspecialty Medicine, Grampians Health, Ballarat, Victoria, Australia; Georgina Humphreys, Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Hazel Ashurst, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Rebekah Burrow, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; George O Adjei, Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, Accra, Ghana; Martin Adjuik, Navrongo Health Research Centre, Navrongo, Ghana and INDEPTH NETWORK Secretariat, Accra, Ghana; Nicholas M Anstey, Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Anup Anvikar, National Institute of Malaria Research, New Delhi, India; Kevin J Baird, Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK and Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia; Bridget E Barber, Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia and Infectious Diseases Society Sabah-Menzies School of Health Research -Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia; Hubert Barennes, Agence Nationale de Recherche sur le Sida (ANRS) and Unité d’Epidémiologie d’Intervention Centre Muraz, Bobo Dioulasso, Burkina Faso and Institut Francophone pour la Médecine Tropicale, Vientiane Lao PDR; Elisabeth Baudin, Epicentre, Paris; David J Bell, Liverpool School of Tropical Medicine, Liverpool, UK and Malawi-Liverpool-Wellcome Clinical Research Programme; Delia Bethell, US Army Medical Component-Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand; Tran Quang Binh, Department of Tropical Diseases, Cho Ray Hospital, Ho Chi Minh City, Vietnam; Isabelle Borghini—Fuhrer, Medicines for Malaria Venture, Geneva, Switzerland; Cindy S Chu, Department of Medicine, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Medicine, University of Oxford, United Kingdom; Andre Daher, Institute of Drug Technology (Farmanguinhos), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil and Vice-presidency of Research and Reference Laboratories, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil and Liverpool School of Tropical Medicine, Liverpool, UK; Umberto D’Alessandro, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine; Debashish Das, Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Worldwide Antimalarial Resistance Network, WWARN and Centre for Tropical Medicine, Nufeld Department of Medicine, University of Oxford, Oxford, United Kingdom; Timothy ME Davis, School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia; Peter J de Vries, Department of Internal Medicine, Tergooi Hospital, Hilversum, the Netherlands; Abdoulaye A Djimde, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Bamako, Mali; Arjen M Dondorp, Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Grant Dorsey, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Jean-François F Faucher, Service des maladies infectieuses et tropicales, CHU de Limoges, France and Inserm, U1094, EpiMaCT—Epidemiology of chronic diseases in tropical zone, Limoges, France and Infectious diseases and tropical medicine department, Limoges University Hospital, Limoges, France; Carole Fogg,Epicentre, Paris, France and School of Health Sciences, University of Southampton, UK; Oumar Gaye, Department of Medical Parasitology, Faculty of Medicine, University Cheikh Anta Diop, Dakar, Senegal; Matthew Grigg, Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Christoph Hatz, Swiss Tropical and Public Health Institute, Allschwil, Switzerland and University of Basel, Basel, Switzerland; Piet A Kager, Centre for Infection and Immunity Amsterdam (CINEMA), Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, the Netherlands; Marcus Lacerda, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil and Instituto Leônidas & Maria Deane, Fiocruz, Brasil; Moses Laman, School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia and Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Andreas Mårtensson, Department of Women’s and Children’s Health, International Maternal and Child health (IMCH), Uppsala University, Uppsala, Sweden; Herve Ignace Eby Menan, Department of Parasitology, Faculty of Pharmacy, University of Cocody, Abidjan, Côte d’Ivoire; Wuelton M Monteiro, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil and Universidade do Estado do Amazonas, Manaus, Brazil; Brioni R Moore, Curtin Medical School, Curtin University, Perth, Australia and Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Francois Nosten, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Bernhards Ogutu, Centre for Clinical Research, Kenya Medical Research Institute, United States Army Medical Research Unit, Kisumu, Kenya; Lyda Osorio, CIDEIM International Center for Medical Research and Training, Cali-Colombia; Louis K Penali, Malariology Department, Institut Pasteur, Abidjan, Côte d’Ivoire; Dhelio B Pereira, Centro de Pesquisa em Medicina Tropical de Rondônia (CEPEM), Porto Velho, Rondônia, Brazil and Universidade Federal de Rondônia (UNIR), Porto Velho, Rondônia, Brazil; Awab G Rahim, Medical Faculty, Nangarhar University, Jalalabad Afghanistan and MORU Tropical Health Network, Bangkok, Thailand; Michael Ramharter, Department of Tropical Medicine Bernhard Nocht Institute for Tropical Medicine & I. Dep. of Medicine, University Medical Center Hamburg-Eppendorf; Issaka Sagara, Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, University of Bamako, Bamako, Mali; Birgit Schramm, Epicentre, Paris, France; Lorenz Seidlein, Farafenni Field Station, Medical Research Council Laboratories, The Gambia and Mahidol Oxford University Research Unit (MORU), Mahidol University, Bangkok, Thailand; Andre M Siqueira, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil and Programa de Pós-graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil and Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Sodiomon B Sirima, Groupe de Recherche Action en Santé (GRAS), Ouagadougou BURKINA FASO; Peter Starzengruber, Institute of Specifc Prophylaxis and Tropical Medicine, Medical University of Vienna,Austria and Department of Laboratory Medicine, Division of Clinical Microbiology, Medical University of Vienna, Vienna, Austria; Inge Sutanto, Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; Walter R Taylor, Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand; Ofanan A Toure, Malariology Department, Institut Pasteur, Abidjan, Côte d’Ivoire; Jürg Utzinger, Swiss Tropical and Public Health Institute, Allschwil, Switzerland and University of Basel, Basel, Switzerland; Innocent Valea, Unité de Recherche Paludisme et Maladies Tropicales Négligées, Centre Muraz, Bobo-Dioulasso, Burkina Faso and Institut de Recherche en Sciences de la Santé, Unité de Recherche Clinique de Nanoro, Nanoro, Burkina Faso; Giovanni Valentini, Research and Development Department, Alfasigma S,p.A; Nicholas J White, Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK and Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Timothy William, Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia and Gleneagles Hospital, Kota Kinabalu, Sabah, Malaysia; Charles J Woodrow, Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Caitlin L Richmond, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK;Philippe J Guerin, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Ric N Price, Global and Tropical Health Division Menzies School of Health Research Charles Darwin University and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK and WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK; Kasia Stepniewska, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK. We thank all patients and staf who participated in these clinical trials at all the sites and the WWARN team for technical and administrative support. We specifcally acknowledge the following investigators: Babacar Faye, Tran T Hien, Natalie Strub-Wourgaft, Khadime Sylla, Roger CK Tine. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as ofcial, or as refecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25.
Author
Affilliation
Abstract
Background: The World Health Organization (WHO) recommends that when peripheral malarial parasitaemia is quantified by thick film microscopy, an actual white blood cell (WBC) count from a concurrently collected blood sample is used in calculations. However, in resource-limited settings an assumed WBC count is often used instead. The aim of this study was to describe the variability in WBC count during acute uncomplicated malaria, and estimate the impact of using an assumed value of WBC on estimates of parasite density and clearance. Methods: Uncomplicated malaria drug efficacy studies that measured WBC count were selected from the WorldWide Antimalarial Resistance Network data repository for an individual patient data meta-analysis of WBC counts. Regression models with random intercepts for study-site were used to assess WBC count variability at presentation and during follow-up. Inflation factors for parasitaemia density, and clearance estimates were calculated for methods using assumed WBC counts (8000 cells/µL and age-stratified values) using estimates derived from the measured WBC value as reference.
Results: Eighty-four studies enrolling 27,656 patients with clinically uncomplicated malaria were included. Geometric mean WBC counts (× 1000 cells/µL) in age groups < 1, 1-4, 5-14 and ≥ 15 years were 10.5, 8.3, 7.1, 5.7 and 7.5, 7.0, 6.5, 6.0 for individuals with falciparum (n = 24,978) and vivax (n = 2678) malaria, respectively. At presentation, higher WBC counts were seen among patients with higher parasitaemia, severe anaemia and, for individuals with vivax malaria, in regions with shorter regional relapse periodicity. Among falciparum malaria patients, using an assumed WBC count of 8000 cells/µL resulted in parasite density underestimation by a median (IQR) of 26% (4-41%) in infants < 1 year old but an overestimation by 50% (16-91%) in adults aged ≥ 15 years. Use of age-stratified assumed WBC values removed systematic bias but did not improve precision of parasitaemia estimation. Imprecision of parasite clearance estimates was only affected by the within-patient WBC variability over time, and remained < 10% for 79% of patients. Conclusions: Using an assumed WBC value for parasite density estimation from a thick smear may lead to underdiagnosis of hyperparasitaemia and could adversely affect clinical management; but does not result in clinically consequential inaccuracies in the estimation of the prevalence of prolonged parasite clearance and artemisinin resistance.
Publisher
BioMed Central
Citation
WYNBERG, Elke et al. Variability in white blood cell count during uncomplicated malaria and implications for parasite density estimation: a WorldWide Antimalarial Resistance Network individual patient data meta-analysis. Malaria Journal, v. 22, n. 174, p. 1-16, Jun. 2023.DOI
10.1186/s12936-023-04583-6ISSN
1475-2875Notes
Andre M. Siqueira - Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, AM, Brazil / Universidade do Estado do Amazonas. Programa de Pós-graduação em Medicina Tropical. Manaus, AM, Brazil / Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em Doenças Febris Agudas. Rio de Janeiro, RJ, Brazil.Andre Daher - Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos (Farmanguinhos). Rio de Janeiro, RJ, Brazil / Fundação Oswaldo Cruz. Presidência. Vice-presidência de Laboratórios de Pesquisa e Referência. Rio de Janeiro, RJ, Brazil / Liverpool School of Tropical Medicine. Liverpool, UK.
Marcus Lacerda - Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brazil / Fundação Oswaldo Cruz. Instituto Leônidas & Maria Deane. Manaus, AM, Brasil.
Members of WWARN White Blood Cell Count in Malaria Study Group: Elke Wynberg, Department of Infectious Diseases, Public Health Service of Amsterdam, Amsterdam, the Netherlands; Robert J Commons, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia and General and Subspecialty Medicine, Grampians Health, Ballarat, Victoria, Australia; Georgina Humphreys, Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Hazel Ashurst, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Rebekah Burrow, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; George O Adjei, Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, Accra, Ghana; Martin Adjuik, Navrongo Health Research Centre, Navrongo, Ghana and INDEPTH NETWORK Secretariat, Accra, Ghana; Nicholas M Anstey, Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Anup Anvikar, National Institute of Malaria Research, New Delhi, India; Kevin J Baird, Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK and Eijkman-Oxford Clinical Research Unit, Jakarta, Indonesia; Bridget E Barber, Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia and Infectious Diseases Society Sabah-Menzies School of Health Research -Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia; Hubert Barennes, Agence Nationale de Recherche sur le Sida (ANRS) and Unité d’Epidémiologie d’Intervention Centre Muraz, Bobo Dioulasso, Burkina Faso and Institut Francophone pour la Médecine Tropicale, Vientiane Lao PDR; Elisabeth Baudin, Epicentre, Paris; David J Bell, Liverpool School of Tropical Medicine, Liverpool, UK and Malawi-Liverpool-Wellcome Clinical Research Programme; Delia Bethell, US Army Medical Component-Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS), Bangkok, Thailand; Tran Quang Binh, Department of Tropical Diseases, Cho Ray Hospital, Ho Chi Minh City, Vietnam; Isabelle Borghini—Fuhrer, Medicines for Malaria Venture, Geneva, Switzerland; Cindy S Chu, Department of Medicine, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Medicine, University of Oxford, United Kingdom; Andre Daher, Institute of Drug Technology (Farmanguinhos), Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil and Vice-presidency of Research and Reference Laboratories, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil and Liverpool School of Tropical Medicine, Liverpool, UK; Umberto D’Alessandro, MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine; Debashish Das, Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Worldwide Antimalarial Resistance Network, WWARN and Centre for Tropical Medicine, Nufeld Department of Medicine, University of Oxford, Oxford, United Kingdom; Timothy ME Davis, School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia; Peter J de Vries, Department of Internal Medicine, Tergooi Hospital, Hilversum, the Netherlands; Abdoulaye A Djimde, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies of Bamako, Bamako, Mali; Arjen M Dondorp, Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Grant Dorsey, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Jean-François F Faucher, Service des maladies infectieuses et tropicales, CHU de Limoges, France and Inserm, U1094, EpiMaCT—Epidemiology of chronic diseases in tropical zone, Limoges, France and Infectious diseases and tropical medicine department, Limoges University Hospital, Limoges, France; Carole Fogg,Epicentre, Paris, France and School of Health Sciences, University of Southampton, UK; Oumar Gaye, Department of Medical Parasitology, Faculty of Medicine, University Cheikh Anta Diop, Dakar, Senegal; Matthew Grigg, Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia; Christoph Hatz, Swiss Tropical and Public Health Institute, Allschwil, Switzerland and University of Basel, Basel, Switzerland; Piet A Kager, Centre for Infection and Immunity Amsterdam (CINEMA), Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, the Netherlands; Marcus Lacerda, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil and Instituto Leônidas & Maria Deane, Fiocruz, Brasil; Moses Laman, School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia and Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Andreas Mårtensson, Department of Women’s and Children’s Health, International Maternal and Child health (IMCH), Uppsala University, Uppsala, Sweden; Herve Ignace Eby Menan, Department of Parasitology, Faculty of Pharmacy, University of Cocody, Abidjan, Côte d’Ivoire; Wuelton M Monteiro, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil and Universidade do Estado do Amazonas, Manaus, Brazil; Brioni R Moore, Curtin Medical School, Curtin University, Perth, Australia and Medical School, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia; Francois Nosten, Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Bernhards Ogutu, Centre for Clinical Research, Kenya Medical Research Institute, United States Army Medical Research Unit, Kisumu, Kenya; Lyda Osorio, CIDEIM International Center for Medical Research and Training, Cali-Colombia; Louis K Penali, Malariology Department, Institut Pasteur, Abidjan, Côte d’Ivoire; Dhelio B Pereira, Centro de Pesquisa em Medicina Tropical de Rondônia (CEPEM), Porto Velho, Rondônia, Brazil and Universidade Federal de Rondônia (UNIR), Porto Velho, Rondônia, Brazil; Awab G Rahim, Medical Faculty, Nangarhar University, Jalalabad Afghanistan and MORU Tropical Health Network, Bangkok, Thailand; Michael Ramharter, Department of Tropical Medicine Bernhard Nocht Institute for Tropical Medicine & I. Dep. of Medicine, University Medical Center Hamburg-Eppendorf; Issaka Sagara, Malaria Research and Training Center, Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, University of Bamako, Bamako, Mali; Birgit Schramm, Epicentre, Paris, France; Lorenz Seidlein, Farafenni Field Station, Medical Research Council Laboratories, The Gambia and Mahidol Oxford University Research Unit (MORU), Mahidol University, Bangkok, Thailand; Andre M Siqueira, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil and Programa de Pós-graduação em Medicina Tropical, Universidade do Estado do Amazonas, Manaus, Brazil and Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Sodiomon B Sirima, Groupe de Recherche Action en Santé (GRAS), Ouagadougou BURKINA FASO; Peter Starzengruber, Institute of Specifc Prophylaxis and Tropical Medicine, Medical University of Vienna,Austria and Department of Laboratory Medicine, Division of Clinical Microbiology, Medical University of Vienna, Vienna, Austria; Inge Sutanto, Department of Parasitology, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia; Walter R Taylor, Mahidol Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand; Ofanan A Toure, Malariology Department, Institut Pasteur, Abidjan, Côte d’Ivoire; Jürg Utzinger, Swiss Tropical and Public Health Institute, Allschwil, Switzerland and University of Basel, Basel, Switzerland; Innocent Valea, Unité de Recherche Paludisme et Maladies Tropicales Négligées, Centre Muraz, Bobo-Dioulasso, Burkina Faso and Institut de Recherche en Sciences de la Santé, Unité de Recherche Clinique de Nanoro, Nanoro, Burkina Faso; Giovanni Valentini, Research and Development Department, Alfasigma S,p.A; Nicholas J White, Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK and Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Timothy William, Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia and Gleneagles Hospital, Kota Kinabalu, Sabah, Malaysia; Charles J Woodrow, Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Caitlin L Richmond, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK;Philippe J Guerin, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK; Ric N Price, Global and Tropical Health Division Menzies School of Health Research Charles Darwin University and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK and WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK; Kasia Stepniewska, WorldWide Antimalarial Resistance Network (WWARN), Oxford, UK and Centre for Tropical Medicine and Global Health, Nufeld Department of Clinical Medicine, University of Oxford, Oxford, UK. We thank all patients and staf who participated in these clinical trials at all the sites and the WWARN team for technical and administrative support. We specifcally acknowledge the following investigators: Babacar Faye, Tran T Hien, Natalie Strub-Wourgaft, Khadime Sylla, Roger CK Tine. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as ofcial, or as refecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25.
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