The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis

Autoři: Andria Mousa aff001;  Abdullah Al-Taiar aff002;  Nicholas M. Anstey aff003;  Cyril Badaut aff005;  Bridget E. Barber aff003;  Quique Bassat aff008;  Joseph D. Challenger aff001;  Aubrey J. Cunnington aff013;  Dibyadyuti Datta aff014;  Chris Drakeley aff015;  Azra C. Ghani aff001;  Victor R. Gordeuk aff016;  Matthew J. Grigg aff003;  Pierre Hugo aff017;  Chandy C. John aff014;  Alfredo Mayor aff008;  Florence Migot-Nabias aff018;  Robert O. Opoka aff019;  Geoffrey Pasvol aff020;  Claire Rees aff021;  Hugh Reyburn aff015;  Eleanor M. Riley aff015;  Binal N. Shah aff016;  Antonio Sitoe aff009;  Colin J. Sutherland aff015;  Philip E. Thuma aff023;  Stefan A. Unger aff024;  Firmine Viwami aff026;  Michael Walther aff027;  Christopher J. M. Whitty aff015;  Timothy William aff028;  Lucy C. Okell aff001
Působiště autorů: MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom aff001;  School of Community & Environmental Health, College of Health Sciences, Old Dominion University, Norfolk, Virginia, United States of America aff002;  Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia aff003;  Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia aff004;  Unité de Biothérapie Infectieuse et Immunité, Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge, France aff005;  Unité des Virus Emergents (UVE: Aix-Marseille Univ—IRD 190—Inserm 1207—IHU Méditerranée Infection), Marseille, France aff006;  QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia aff007;  ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain aff008;  Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique aff009;  ICREA, Barcelona, Spain aff010;  Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Sant Joan de Déu (University of Barcelona), Barcelona, Spain aff011;  Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain aff012;  Section of Paediatric Infectious Disease, Department of Infectious Disease, Imperial College London, United Kingdom aff013;  Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America aff014;  Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom aff015;  Sickle Cell Center, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America aff016;  Medicines for Malaria Venture, Geneva, Switzerland aff017;  Université de Paris, MERIT, IRD, Paris, France aff018;  Department of Paediatrics and Child Health, Makerere University School of Medicine, Kampala, Uganda aff019;  Imperial College London, Department of Life Sciences, London, United Kingdom aff020;  Centre for Global Public Health, Institute of Population Health Sciences, Barts & The London School of Medicine & Dentistry, London, United Kingdom aff021;  Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom aff022;  Macha Research Trust, Choma, Zambia aff023;  Department of Child Life and Health, University of Edinburgh, United Kingdom aff024;  Department of Respiratory Medicine, Royal Hospital for Sick Children, Edinburgh, United Kingdom aff025;  Institut de Recherche Clinique du Bénin (IRCB), Cotonou, Benin aff026;  Medical Research Council Unit, Fajara, The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, The Gambia aff027;  Infectious Diseases Society Sabah-Menzies School of Health Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia aff028;  Gleneagles Hospital, Kota Kinabalu, Sabah, Malaysia aff029
Vyšlo v časopise: The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis. PLoS Med 17(10): e32767. doi:10.1371/journal.pmed.1003359
Kategorie: Research Article



Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as ‘test-and-treat’ policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM.

Methods and findings

A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case–control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle–Ottawa scale, and all studies were ranked as ‘Good’, scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07–1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92–4.06; p < 0.001) for a delay of 2–3 days and 5.46 (95% CI: 3.49–8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24–4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70–9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify.


Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

Klíčová slova:

anémia – Antimalarials – Blood transfusion – Cerebral malaria – Fevers – Health care facilities – Malaria – Medical risk factors


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2020 Číslo 10
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