TY - JOUR
T1 - The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria
T2 - A systematic review and a pooled multicentre individual-patient meta-analysis
AU - Mousa, Andria
AU - Al-Taiar, Abdullah
AU - Anstey, Nicholas M.
AU - Badaut, Cyril
AU - Barber, Bridget E.
AU - Bassat, Quique
AU - Challenger, Joseph D.
AU - Cunnington, Aubrey J.
AU - Datta, Dibyadyuti
AU - Drakeley, Chris
AU - Ghani, Azra C.
AU - Gordeuk, Victor R.
AU - Grigg, Matthew J.
AU - Hugo, Pierre
AU - John, Chandy C.
AU - Mayor, Alfredo
AU - Migot-Nabias, Florence
AU - Opoka, Robert O.
AU - Pasvol, Geoffrey
AU - Rees, Claire
AU - Reyburn, Hugh
AU - Riley, Eleanor M.
AU - Shah, Binal N.
AU - Sitoe, Antonio
AU - Sutherland, Colin J.
AU - Thuma, Philip E.
AU - Unger, Stefan A.
AU - Viwami, Firmine
AU - Walther, Michael
AU - Whitty, Christopher J.M.
AU - William, Timothy
AU - Okell, Lucy C.
N1 - Funding Information:
Funding:A.Mo.issupportedbytheUKMedical ResearchCouncil(Grantnumber:G98669,https:// mrc.ukri.org/). LCO acknowledges funding from a
Funding Information:
A.Mo. is supported by the UK Medical Research Council (Grant number: G98669, https:// mrc.ukri.org/). LCO acknowledges funding from a UK Royal Society Dorothy Hodgkin fellowship, Medicines for Malaria Venture, and the Bill & Melinda Gates Foundation. A.Mo., LCO, ACG, and JDC acknowledge joint Centre funding from the UK Medical Research Council and DFID under the MRC/DFID Concordat agreement and that is also part of the EDCTP2 programme supported by the European Union (MR/R015600/1). NMA and MJG are supported by the National Health and Medical Research Council of Australia (Fellowships 11355820 and 1138860; Program Grants 1037304 and 1132975). A.Ma. and QB acknowledge ISGlobal, which is a member of the CERCA Programme (Generalitat de Catalunya, http://cerca. cat/en/suma/). This research is part of ISGlobal’s Program on the Molecular Mechanisms of Malaria, which is partially supported by the Fundación Ramón Areces. A.Ma., QB, and AS also acknowledge the Manhiça Health Research Centre (CISM), which is supported by the Government of Mozambique and the Spanish Agency for International Development (AECID). A.Ma. is supported by the Departament d’Universitats i Recerca de la Generalitat de Catalunya, Agència de Gestió d’Ajuts Universitaris i de Recerca (2017SGR664). For the studies conducted in Uganda, CCJ acknowledges the National Institutes of Health (Fogarty Institute grant R21 TW-006794), the National Institute of Neurological Disorders and Stroke, and the Fogarty International Center (grants R01NS055349 and D43 NS078280). For the study conducted in Macha, Zambia, VRG acknowledges the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (grants 1 R01 AI44857 and AI051306); the National Heart, Lung, and Blood Institute and the Office of Research on Minority Health at the National Institutes of Health (grant UH1-HL03679); and the National Institute of Research Resources, Howard University General Clinical Research Center (grant MO1-RR10284). PET received salary support from the NIH/NIAID grant 1 R01 A144857 that funded the study conducted in Macha, Zambia. AJC was supported by the Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement that is also part of the EDCTP2 program supported by the European Union [MR/L006529/1 and G0701427]. ER, CD, and HR acknowledge funding from the UK Medical Research Council and DFID under the MRC/DFID Concordat agreement (grant reference number G9901439) for the studies in North-eastern Tanzania. For the study conducted in Benin, FMN, CB, and FV acknowledge the French Agence Nationale de la Recherche (project RESAs, ANR-08-MIE-031). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank all participants and everyone involved in the collection, management, and analysis of the data in the original or earlier studies, including Amina Farah, Frank Mtei, and Jamie Griffin, and Peter Winskill for providing advice on methodology.
Publisher Copyright:
© 2020 Mousa et al. 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.
PY - 2020/10/19
Y1 - 2020/10/19
N2 - Background 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. Conclusions 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.
AB - Background 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. Conclusions 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.
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U2 - 10.1371/journal.pmed.1003359
DO - 10.1371/journal.pmed.1003359
M3 - Article
C2 - 33075101
AN - SCOPUS:85093910700
SN - 1549-1277
VL - 17
JO - PLoS medicine
JF - PLoS medicine
IS - 10
M1 - e1003359
ER -